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A new method of peak detection for analysis of comprehensive two-dimensional

gas chromatography mass spectrometry data
Article in The Annals of Applied Statistics · August 2014

DOI: 10.1214/14-AOAS731
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Ann Appl Stat. 2014 June ; 8(2): 1209–1231.
A NEW METHOD OF PEAK DETECTION FOR ANALYSIS OF

COMPREHENSIVE TWO-DIMENSIONAL GAS
CHROMATOGRAPHY MASS SPECTROMETRY DATA*
Seongho Kim,
Biostatistics Core, Karmanos Cancer Insitute, Wayne State University, Detroit, MI 48201, USA
Ming Ouyang,
Department of Computer Science, University of Massachusetts Boston Boston, MA 02125, USA
Jaesik Jeong,
Department of Statistics, Chonnam National University, Gwangju 500757, Korea
Changyu Shen, and

Department of Biostatistics, Indiana University, Indianapolis, IN 46202, USA
Xiang Zhang
Department of Chemistry, University of Louisville, Louisville, KY 40292, USA
Wayne State University, University of Massachusetts Boston, Chonnam National University,

Indiana University, and University of Louisville
Abstract
We develop a novel peak detection algorithm for the analysis of comprehensive two-dimensional
gas chromatography time-of-flight mass spectrometry (GC×GC-TOF MS) data using normal-
exponential-Bernoulli (NEB) and mixture probability models. The algorithm first performs
baseline correction and denoising simultaneously using the NEB model, which also defines peak
regions. Peaks are then picked using a mixture of probability distribution to deal with the co-
eluting peaks. Peak merging is further carried out based on the mass spectral similarities among
the peaks within the same peak group. The algorithm is evaluated using experimental data to study
the effect of different cut-offs of the conditional Bayes factors and the effect of different mixture
models including Poisson, truncated Gaussian, Gaussian, Gamma, and exponentially modified
Gaussian (EMG) distributions, and the optimal version is introduced using a trial-and-error
approach. We then compare the new algorithm with two existing algorithms in terms of compound
identification. Data analysis shows that the developed algorithm can detect the peaks with lower
false discovery rates than the existing algorithms, and a less complicated peak picking model is a
promising alternative to the more complicated and widely used EMG mixture models.
SUPPLEMENTARY MATERIAL
Supplement to peak detection in GC×GC: (http://lib.stat.cmu.edu/aoas/). A brief introduction to GC×GC-TOF MS data, derivations of
Equations (2.3) and (2.11), the pdfs of five probability models, and Figures S1-S8 are in this Supplementary Information.
Corresponding Author’s: [email protected]; [email protected].
*Supported in part by NSF grant DMS-1312603, NIH Grants 1RO1GM087735, R21ES021311 and P30 CA022453.
Kim et al. Page 2
Keywords
Bayes factor; GC×GC-TOF MS; metabolomics; mixture model; normal-exponential-Bernoulli
(NEB) model; peak detection
1. Introduction
Multiple analytical approaches such as liquid chromatography mass spectrometry (LC-MS),
gas chromatography mass spectrometry (GC-MS), and nuclear magnetic resonance
spectroscopy (NMR) have been employed for the comprehensive characterization of
metabolites in biological systems. One such powerful approach is comprehensive two-
dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOF MS).
Unlike other existing analytical platforms, GC×GC-TOF MS provides much increased
separation capacity, chemical selectivity and sensitivity for the analysis of metabolites
present in complex samples. The information-rich output content of GC×GC-TOF MS data
has huge potential in metabolite profiling, identification, quantification, and metabolic
network analysis (Castillo et al., 2011; Jeong et al., 2011; Kim et al., 2011; Pierce et al.,
2005; Sinha et al., 2004).
Metabolites analyzed on a GC×GC-TOF MS system are first separated on two-dimensional

GC columns and then subjected to a mass spectrometer, which is usually equipped with an
electron ionization (EI) ion source. The EI process fragments the metabolite’s molecular
ions and results in fragment ion mass spectrum. For metabolite identification and
quantification using the EI mass spectra, the first step is to reduce the instrument data, i.e., a
collection of EI mass spectra, to chromatographic peaks. To help readers understand the
GC×GC-TOF MS data, a brief introduction is given in the Supplementary Information.
Although numerous algorithms have been developed for peak detection in one dimensional
GC-MS data (Dixon et al., 2006; Nicolè et al., 2012; O’Callaghan et al., 2012; Yang, He,
and Yu, 2009), there are only four algorithms available for the two-dimensional GC-MS
(Peters et al., 2007; Reichenbach et al., 2005; Vivó-Truyols, 2012) including commercial
software ChromaTOF from LECO company. However, none of these software packages is
publicly available yet, except ChromaTOF that is commercially embedded in the GC×GC-
TOF MS instrument. It is therefore highly desirable to develop publicly available peak
detection methods for the analysis of GC×GC-TOF MS data. On the other hand, the existing
peak detection algorithms for the analysis of GC×GC-TOF MS data perform baseline
correction and denoising separately, which may greatly increase the risk of introducing
errors from each independent stage. In fact, Wang et al. (2008) introduced a reversible jump
Markov chain Monte Carlo (RJ-MCMC)-based peak detection algorithm to perform
simultaneous baseline, denoising and peak identification for analysis of one-dimensional
surface enhanced laser desorption/ionization (SELDI) MS data and demonstrated that the
simultaneous process reduces false discovery rate. However, in practice, the use of
applications of RJ-MCMC is limited due to that prior distributions should be appropriately
assigned in order to design an effective RJ-MCMC algorithm and make posterior
distributions of parameters computationally tractable and that constructing an MCMC chain
Kim et al. Page 3
is in general computationally extensive. Yang et al. (2009) compared the performance of

peak detection among several peak detection algorithms for one-dimensional matrix-assisted
laser desorption/ionization (MALDI) MS data and showed that the continuous wavelet-
based (CWT) algorithm, which has simultaneous baseline and denoising, provides the best
performance, but it is still a major challenge to compute accurate peak abundance (area),
which is very important in compound quantification, due to its model-free approach.
Furthermore, the existing algorithms require manually assigned signal-to-noise ratio (SNR)
threshold and/or denoising parameters that are usually not optimized in the existing peak
detection algorithms, resulting in a high rate of false-positive and/or false-negative peaks.
To avoid the aforementioned difficulties in analysis of GC×GC-TOF MS data, we propose a

novel peak detection algorithm using a normal-exponential-Bernoulli (NEB) model and
mixture probability models, and the developed R package msPeak is publicly-available at
http://mrr.sourceforge.net. The developed algorithm is composed of the following
components: (i) the proposed NEB model performs simultaneous baseline correction and
denoising, followed by finding the potential peak regions using a conditional Bayes factor-
based statistical test, (ii) the peak picking and area calculations are carried out by fitting
experimental data with a mixture of probability model, and (iii) the detected peaks
originated from the same compound are further merged based on mass spectral similarity.
The advantages of the proposed method are that the proposed NEB-based preprocessing
requires no manually assigned SNR threshold and denoising parameters from users, which
makes it easy to use; and, instead of searching for the potential peaks using the entire data,
the proposed algorithm reduces the entire data to peak regions using a conditional Bayes
factor of the test, eliminating the possible computational burden as well as improving the
quality of peak abundance (area). The developed algorithm is further compared with two
existing algorithms in terms of compound identification.
Besides, we investigated the performance of several probability mixture models for peak
picking based on peak regions identified by the NEB model. It has been known that the
model-based approach measures more accurately peak abundance (area) and the
exponentially modified Gaussian (EMG) probability model performs well for fitting
asymmetric chromatographic peaks and the detection of peak position (Di Marco and
Bombi, 2011; Vivó-Truyols, 2012; Wei et al., 2012). However, to our knowledge, there is
no study to evaluate EMG model by comparing with other possible probability models in
analysis of GC×GC-TOF MS data. To address this, we employed five probability mixture

models: Poisson mixture models (PMM), truncated Gaussian mixture models (tGMM),
Gaussian mixture models (GMM), Gamma mixture models (GaMM), and exponentially
modified Gaussian mixture models (EGMM). Here PMM, GMM, and EGMM were chosen
based on Di Marco and Bombi (2011)’s work, and we proposed two new models, tGMM
and GaMM, as alternatives to GMM and EGMM, respectively.
We hope our research can provide some insight on the following computational/statistical
challenges of the current peak detection approaches: (i) baseline correction and denoising
are performed separately so that there is no way to communicate the information with each
step, (ii) user-defined input values are needed, (iii) entire data are used for peak detection
(compared to our proposed approach that finds peak regions first and then detect peaks), and
Kim et al. Page 4
(iv) there is no comparison analysis for the performance of different chromatographic peak
models.
The rest of the paper is organized as follows. Section 2 presents the proposed peak detection
algorithm and introduces a trial-and-error optimization of the developed algorithm. The real
GC×GC-TOF MS data is described in Section 3. In section 4, we apply the developed
algorithm to real experimental GC×GC-TOF MS data, followed by the comparison with two
existing algorithms in Section 5. In Section 6, we discuss the results and then conclude our
work in Section 7.
2. Algorithms
The proposed peak detection algorithm consists of three components with the following four
steps: finding potential peak regions, simultaneous denoising and baseline correction, peak
picking and area calculation, and peak merging (Supplementary Information Figure S1). The
first two steps are performed by hierarchical statistical models at a time, while the peak
picking and area calculation are carried out by model-based approaches in conjunction with
first derivative test. The peak merging then uses mass spectral similarities to recognize
peaks originated from the same metabolite. The selection of the cut-off value of the
conditional Bayes factor and the probability model is further optimized by a trial-and-error
optimization. On the other hand, when multiple samples are analyzed, each sample will
generate a peak list after peak detection. A cross sample peak list alignment is needed to
recognize chromatographic peaks generated by the same compound in different samples.
Current existing peak-based methods generally perform peak alignment using the mass
spectral similarity and peak position (location) distance (e.g., Kim et al., 2011). This peak
alignment process will generate a matched peak table for downstream data analysis, such as
quantification and network analysis. In this regard, the peak detection process plays an
important role in generating the peak list. It should be noted that, due to either systematic
(technical) or biological variations, some peaks (molecules) may not be detected in all
samples, resulting in an incomplete peak table. There are several remedies to deal with the
issue, such as ignoring missing data, filling in zero, or imputing/estimating missing data
(e.g., Hrydziuszko and Viant, 2012; Liew, Law, and Yan, 2011).
2.1. Finding peak regions

Newton et al. (2001) proposed a hierarchical approach to the microarray data analysis using
gamma-gamma-Bernoulli model. Their purpose was to detect the genes that are
differentially expressed. In this study, we adopted their idea to simultaneously perform
baseline correction and denoising, by replacing the gamma-gamma-Bernoulli model with the
normal-exponential-Bernoulli (NEB) model. The proposed hierarchical NEB model has
three layers. In the first layer, the observed data, Xi, are modeled through the normal
distribution with mean Θi + μ and variance σ2 for each ith total ion chromatogram (TIC),
where i = 1, ⋯, N and N is the number of TICs. Note that a TIC is a chromatogram created
by summing up intensities of all mass spectral peaks collected during a given scan (or a
given instrumental time). In other words, we assume that the noise follows the normal
distribution with mean zero and variance σ2. For simplicity, the homogeneous variance is
assumed in this model. Here Θi is the true signal of the observed signal Xi and μ is either a
Kim et al. Page 5
baseline or a background. The true signal, Θi, is further modeled by the exponential
distribution with mean φ in the second layer. In case that there is only noise, meaning that
no signal is present, the observed signal, Xi, is modeled only with the background and noise
signal. Consequently, Xi follows the normal distribution with mean μ and variance σ2.
In this approach, we pay attention to whether the observed TIC at a given position is
significantly different from background signal. To do this, one more layer is introduced in
the model using a Bernoulli distribution, resulting in the NEB model. The true TICs of some
proportion r are present (i.e., Θi ≠ 0), while others remain at zero (Θi = 0). For positions
where the true TIC is present, we use the following model:
(2.1)
where N D stands for a normal distribution, Xi is an observed TIC at the ith position, Θi is
the true TIC of Xi of the exponential distribution with φ, and μ is the mean background or
baseline with variance σ2. In case that no TIC is present, the background signal follows:
(2.2)
Therefore, the marginal density of Xi when i ≠ 0 is driven by
(2.3)
where Φ(·) is the cumulative distribution function (cdf) of the standard normal distribution.
When Θi = 0, the marginal density of xi becomes the probability density function (pdf) of a
normal distribution with mean μ and variance σ2. The detail derivation of Equation (2.3) can
be found in the Supplementary Information. The loglikelihood l(μ, σ2, φ, r) is
(2.4)
where yi is the value of the binary indicator variable, Yi, at the ith TIC with 0 unless there is
a true significant signal and r is the proportion of the true TICs. As a result, there are four
parameters (μ, σ2, φ, r) along with the indicator variable Yi(i = 1, ⋯, N) to estimate. The
graphical representation of the proposed NEB model is depicted in Figure 1.
Parameter estimation—The EM algorithm (Dempster, Laird, and Rubin, 1977) is

employed to estimate the parameters of Equation (2.4) by considering the indicator variable
Yi(i = 1, ⋯, N) as the latent (or missing) variable. In the E-step, the latent variable Yi(i = 1,
⋯, N) is estimated, after fixing the parameters (μ, σ2, φ, r) at the current estimates, by
(2.5)
To simplify the M-step, the mixture structure has been separated so that the update estimate
of r is the arithmetic mean of ’s and the remaining parameters (μ, σ2, φ) are optimized by a
Kim et al. Page 6
numerical approach such as the R package nlminb. It should be noted that our optimization
does not guarantee a global optimum since the R package nlminb used is a local
optimization. In particular, a Beta(2, 2) is placed as a prior over r to stabilize the
computation as well as to enable a nice interpretation of the output, according to Newton et

al. (2001), resulting in the following r:̂
(2.6)
where N is the total number of TIC. After fixing , the remaining parameters are estimated
by maximizing the loglikelihood as follows:
(2.7)
Finding true signals—The true signals are found by performing the significant test based
on the posterior odds. The posterior odds of signal at the ith TIC are expressed by
(2.8)
The posterior probability of yi given the entire TIC is
(2.9)
by conditional independence of the data at different TICs given the parameter r. Using the
approach in Newton et al. (2001), the posterior odds can be approximated by
(2.10)
where w can be called conditional Bayes factors since the prior odds equal unity, P(yi = 1|x1,
⋯, xN) ≈ p1(xi)r̂ and P(yi = 0|x1, ⋯, xN) ≈ p0(xi)(1-r̂) by approximating Equation (2.9) at
the model r = r̂. According to Jeffreys (1961)’ scales, the three values of 1, 10, and 100 are
used to interpret the posterior odds, meaning that the TICs are selected using three cut-off
values. That is, if the posterior odds of a TIC are less than a selected cut-off value, then this
TIC is considered as a noise by fixing it at zero (i.e., Θi = 0). Otherwise, the TIC will be
preserved for future analysis (i.e., Θi ≠ 0).
2.2. Denoising and baseline correction

Once the significant TICs (true signals) are detected by the posterior odds, the baseline
correction and denoising are performed simultaneously based on the estimated parameters.
That is, under the assumption that the TIC is true signal (Θi ≠ 0), the convoluted TIC, x̂i, is
predicted by the expected true TIC (signal) given an observed TIC, i.e., E(Θi|xi). By doing
Kim et al. Page 7
the calculation described in the Supplementary Information, we can obtain the convoluted
TIC, x̂i, as follows:
(2.11)
where φ and Φ are the probability density and cumulative distribution functions of the
standard normal distribution N D(0, 1), respectively.
2.3. Peak detection and area calculation
After denoising and baseline correction, the vector of predicted TICs, , are
converted into the N1 by N2 matrix D(= [dkl]k=1,⋯,N1;l=1,⋯, N2), where N = N1 · N2. Here
the sizes of the row and column of the matrix D are the same as the intervals of the first and
the second dimension retention times, respectively. In order to detect peaks for each
significant peak region, we employ five different model-based approaches along with the
first derivative test (FDT): Poisson mixture models (PMM), truncated Gaussian mixture
models (tGMM), Gaussian mixture models (GMM), Gamma mixture models (GaMM), and
exponentially modified Gaussian mixture models (EGMM).
The peak area is calculated based on the highest probability density (HPD) regions of 95%
for model-based approaches. We assume that Dk is the kth row vector of the matrix D, where
the size of Dk is N2 and 1 ≤ k ≤ N1, and Dk = {dkl}l=1,⋯,N2. In other words, Dk is a vector of
intensities at each second dimension retention time given the kth first dimension retention
time. Then Dk is partitioned into several nonzero peak regions, i.e.,
, where 1 ≤ k ≤ N; ; 1 ≤ m ≤ M_{k_};
. It is noteworthy that is a nonzero peak region and its intensities zkl’s
are always nonzero.
First derivative test (FDT)—FDT is used to infer the maximum number of components
(peaks) of the mixture probability models. The first derivative is calculated over the
converted nonzero vector with respect to the second dimension retention times to find a
peak, for the given kth first dimension retention time and the mth nonzero peak region where
1 ≤ k ≤ N1 and 1 ≤ m ≤ Mk. By doing so, the local maxima are found with respect to the
second dimension retention time. That is, for each converted vector , we examine zkl
whether it is a local maximum with respect to the second dimension retention time as
follows:
(2.12)
where Ikl is the indicator variable for peaks detected using the second dimension retention
time; 1 indicates a local maximum. In fact, we observed that the first derivative test with
respect to the first dimension retention time has little information in most cases, due to the
Kim et al. Page 8
relatively large value of modulation period compared to the chromatographic peak width in
the first dimension GC. For this reason, we used only the second dimension retention time
for peak picking. It is noteworthy to mention again that we use the FDT only for guessing
the maximum number of the possible peaks and for an initial value of the optimization of the
model-based approach.
Model-based approach—The five different probability models including Poisson,

truncated Gaussian, Gaussian, Gamma, and exponentially modified Gaussian distributions
are employed along with mixture models. For each converted nonzero vector
, a mixture of the selected probability models are fitted to the observed,

convoluted intensities. Suppose fs(·|ξs) is a pdf with a parameter of ξs of the sth component,
where 1 ≤ s ≤ S, ξs is a scalar or a vector, and S is the number of mixture components. Then
the converted nonzero intensity zkl at the kth first dimension retention time is modeled as
follows:
(2.13)
where tl is the second dimension retention time at the lth position, ws is the nonnegative
weight factor of the sth component, , and N D stands for a normal distribution
2
with variance τ . The parameters (ζ, S) are estimated by minimizing −2 times loglikelihood
function:
(2.14)
where , and and are the estimated parameters of the sth component. The
pdf and its parameters for Poisson, truncated Gaussian, Gaussian, Gamma, and
exponentially modified Gaussian can be found in the Supplementary Information.
Then 95% highest probability density (HPD) intervals are calculated with the estimated
and for each kth peak, , and the length of its 95% HPD interval is assigned as
the peak area. As mentioned before, we consider the number of peaks detected by FDT as
the maximum number of peaks that can be detected. Therefore, the number of mixture
components estimated by each model-based approach ( ) always becomes less than or equal
to the number of peaks detected by FDT. Furthermore, the intensities are divided by the total
sum of nonzero intensities in a given peak region for the purpose of normalization since
each model is a probability distribution.
2.4. Peak grouping and merging

It is likely that multiple peaks detected can be from the same compound due to systemic
variations. To correct these multiple peaks, we use the mass spectrum (MS) information by
calculating the MS similarity among the peaks. Since it might be computationally expensive
Kim et al. Page 9
if all the pairwise MS similarities are calculated, we first group the peaks according to their
nonzero peak regions and then merge the peaks having the higher MS similarity using a
user-defined cut-off value, only if these peaks are present in the adjacent nonzero peak
region(s). For instance, assuming that two peaks zkl and zmn belong to the nonzero peak
regions and , respectively, zkl and zmn are considered as members of the same group if
these two peak regions are adjacent to each other. Otherwise, they are assigned to different
groups. The MS similarities among all peaks within the same group are calculated, and the
peak with the highest TIC is selected as the representative peak in case that multiple peaks
have the MS similarities greater than the user defined cut-off value (e.g., 0.95) by replacing
the peak area with the sum of peak areas of all merged peaks.
2.5. Optimal selection of the cut-off value and the probability model
As can be observed in Section 3, the optimal probability mixture model can be different
according to the detected peak regions, so does the cut-off value of the conditional Bayes
factor. For this reason, we further consider a trial-and-error optimization of the developed
algorithm in order to select the optimal cut-off value of the conditional Bayes factor and the
optimal probability mixture model. To do this, three objective functions are considered,
which are mean squared error (MSE), Akaike information criterion (AIC), and Bayesian
information criterion (BIC) that were used in Section 3. That is, given a selected objective
function, we first look for the optimal probability mixture model for each detected peak
region and then find the optimal cut-off value of the conditional Bayes factor by the
minimum of the sums of all the objective functions for each cut-off value. In detail, the
optimal cut-off value is selected by the following trial-and-error optimization:
(2.15)
where ν ∈ {1, 10, 100} is a cut-off value; βm ∈ {PMM, tGMM, GMM, GaMM, EGMM} is
a probability model; and . In particular, the function
is varied with respect to the choice of the objective function:
(2.16)
where ; are the parameter

estimates of a given probability model ; and is the number of the parameters of a
given probability model. For the case that a certain probability model is preferred, we can
just optimize the cut-off value of the conditional Bayes factor by fixing at a user-defined
model. In addition, we can also just optimize the probability model by fixing at a certain
cut-off value. Note that the last two approaches are computationally less expensive.
Kim et al. Page 10
3. GC×GC-MS data and software

To evaluate the performance of the developed peak finding algorithm, an experimental data
set generated from a comprehensive two-dimensional gas chromatography time-of-flight

mass spectrometry (GC×GC-TOF MS) was used. The sample analyzed on GC×GC-TOF
MS is a mixture of 76 compound standards (8270 MegaMix, Restek Corp., Bellefonte, PA)
and C7-C40 n-alkanes (Sigma-Aldrich Corp., St. Louis, MO). The concentration of each
compound in the mixture is 2.5 μg/mL. The mixture was analyzed on a LECO Pegasus 4D
GC×GC-TOF MS instrument (LECO Corporation, St. Joseph, MI, USA) equipped with a
cryogenic modulator. All the statistical analyses were performed using statistical software R
2.13.1 (R Development Core Team, 2012), and the developed R package msPeak is
available at http://mrr.sourceforge.net.
4. Applications
We applied the developed algorithm to the two sets of the experimental GC×GC-TOF MS
data described in the previous section. The first data set is a small region selected from the
experimental data while the second data set is the entire experimental data. The developed
algorithm was further compared with the two existing algorithms, continuous wavelet-based
(CWT) algorithm and ChromaTOF, in terms of compound identification in Section 5.
4.1. Analysis of selected data

For illustration purpose, we selected a small region from the entire experimental data as
shown in Supplementary Information Figure S2(b). Upon this selected data, we performed
the process of peak finding according to the algorithm described in Section 2.
Figure S2(c) displays the results of the NEB model-based significant test as well as
denoising and baseline correction for the selected data. As described in Section 2, the
significant test is rendered by a conditional Bayes factor of the test in Equation (2.10) with
the three different odds (cut-off) values such as 1, 10, and 100. Of these, the largest cut-off
value is the strictest condition in that there are fewer significant TICs. In other words, there
are more TICs of zero in case of the odds of 100. In this figure, the black open circles
represent the original TIC, and the red cross ‘×’, green plus ‘+’, and blue open circles
indicate the convoluted TICs of the odds of 1, 10, and 100, respectively. Figure S2(d) is the
magnified plot of the green box in Figure S2(c). Clearly, we can see that the odds of 1 (red
cross ‘×’) has the most nonzero convoluted TICs as depicted in Figure S2(d). The detected
peak regions are plotted in Figure S3 of Supplementary Information. In Figure S3, the total
number of nonzero peak regions detected is 36, 28, and 27 when the cut-off value of odds is
1, 10, and 100, respectively. As expected, the odds of 1 have the most nonzero peak regions.
Once the nonzero peak regions were detected, we searched for the significant peaks at each
nonzero peak region using five probability mixture models, PMM, tGMM, GMM, GaMM,
and EGMM. As mentioned before, the number of peaks detected by FDT is considered as
the maximum number of peaks to be fitted by each of five probability mixture models. Each
of PMM, tGMM, GMM, GaMM, and EGMM has (S · 1+1), (S · 2+1), (S · 2+1), (S · 2+1),
and (S · 3+1) parameters to estimate, where S is the number of mixture components. Note
Kim et al. Page 11
that the truncated Gaussian distribution has four parameters including the lower and the
upper bounds, but, in this study, these bounds are fixed with the starting and ending indices
of a given nonzero peak region. Only when the number of data points for a given nonzero
peak region is more than or equal to the required number of parameters for a selected
probability model, the normalized intensities are fitted using the probability model.
To evaluate the performance of each probability model for fitting the normalized intensities,
we consider four measures: mean squared error (MSE), −2 times loglikelihood (LL), Akaike
information criterion (AIC), and Bayesian information criterion (BIC). A probability model
is considered as performing better if its MSE, LL, AIC, or BIC is lower. It is noteworthy that
LL is given only as a reference and will not be directly used for comparison since each
model is not nested. The results of fitting the normalized intensities using the proposed five
probability mixture models are reported in Table 1.
In case of odds of 1, the MSE, LL, and AIC of EGMM are the lowest and these of PMM are
the largest. However, the lowest BIC happens with PMM that has the smallest number of
parameters to estimate. On the other hand, when the cut-off value of odds is 10, the MSEs
are dramatically reduced up to five times lower than these of odds 1. In this case, tGMM has
the lowest MSE, and the largest MSE still occurs when PMM is employed. However,
EGMM has the lowest LL, AIC, and BIC. Interestingly, the overall MSE becomes worse
than that of odds 1, when the cut-off value increases to 100. Nevertheless, its trend is similar
to that of odds 10. Overall, in terms of MSE, a better fitting is achieved when 10 is
considered as the cut-off value of odds and when the truncated Gaussian mixture model is
used.
Figure 2 shows the cases when each probability model performs best among other mixture
models in terms of MSE, when the cut-off value is 10. That is, Figures 2(a)-2(e) display the
fitted curves when PMM, tGMM, GMM, GaMM, and EGMM fit the normalized intensities
with the lowest MSE, respectively. In Figure 2(a), PMM has the largest number of peaks
detected, which is four as FDT does, while PMM has the lowest MSE (MSE (×105) = 0.06
(PMM), 0.09 (tGMM), 0.10 (GMM), 1.19 (GaMM), 0.21 (EGMM)). Although there is only
one peak in this figure, but only EGMM detected one peak. tGMM and GMM have the
peaks in the very similar position as expected. GaMM has two peaks detected with one peak
positioned at the upper bound of the second dimension retention time. This peak region
corresponds to the peak region (a) in Figure 2(f). tGMM has the lowest MSE in Figure 2(b)
(MSE (×105) = 83.01 (PMM), 3.20 (tGMM), 6.08 (GMM), 7.40 (GaMM), 5.56 (EGMM)).
In this case, all the detected peaks are located at the same position except for GaMM, which
is shifted to the left. PMM has much larger MSE, indicating the worst fitted curve to the data
points. Figure 2(c) has the similar peak shape to that of Figure 2(a), while GMM is the best
fitted model and is marginally better than tGMM at the third decimal point in this case
(MSE (×105) = 0.88 (PMM), 0.36 (tGMM), 0.36 (GMM), 0.69 (GaMM), 0.54 (EGMM)).
Likewise, all the probability models detected two or more peaks except for EGMM, even
though there is only one chromatographic peak. Its index of peak region is (c) as shown in
Figure 2(f). Three chromatographic peaks are observed in Figure 2(d). PMM and EGMM
detect no peak in the beginning of the curve while the other models correctly detect this
peak. GaMM has the lowest MSE (MSE (×105) = 1.90 (PMM), 0.75 (tGMM), 0.76 (GMM),
Kim et al. Page 12
0.46 (GaMM), 0.62 (EGMM)). The case that EGMM has the lowest MSE is depicted in
Figure 2(e) (MSE (×105) = 0.49 (PMM), 0.36 (tGMM), 0.35 (GMM), 0.24 (GaMM), 0.15
(EGMM)). Only tGMM and GMM resolve the peak in the middle of the curve although
their peak positions are shifted to the left. Overall, EGMM fits the normalized intensities
well with the smaller MSE, but tGMM and GMM have a better capability of detecting the
peaks that have a relatively smaller peak height.
The detected peaks are indicated in the selected GC×GC-TOF MS data as shown in
Supplementary Information Figure S4. In this figure, the dotted red box represents the
nonzero peak region detected from the proposed NEB model, and the grey contour is plotted
based on the original TIC. When the cut-off value of odds is 1, the total number of peaks
detected by PMM, tGMM, GMM, GaMM, and EGMM is 61, 53, 53, 60, and 47,
respectively, as shown in Figure S4(a). Of these probability models, PMM has the largest
number of detected peaks and EGMM has the smallest number of peaks detected. In case of
odds 10 and 100, PMM and GaMM have the largest numbers of peaks detected out of five
probability mixture models, which are 43 and 40 for odds of 10 and 100, respectively.
EGMM still has the smallest number of detected peaks of 37 as can be seen in Figures S4(c)
and S4(e). For illustration purpose, the detected peaks when the cut-off is 10 are depicted in
Figure 2(f). Comparing Figure S4(a) with Figures S4(c) and S4(e), it can be seen that the
peak regions of small sizes have vanished in Figures S4(c) and S4(e) when the odds
increase. The detected peaks after peak merging are shown in Figures S4(b), S4(d), and
S4(f). The peak merging dramatically reduced the number of detected peaks up to the one-
third of the number of peaks before peak merging.
Furthermore, three interesting points can be observed. One is that the cut-off value has little
effect on the overall performance of peak detection, although the odds of 10 give us the best
average performance. The second is that the peaks detected by each probability model
become similar to each other after peak merging. The last is that the detected peaks by
EGMM are very similar to these by PMM, after peak merging, although PMM has the worst
MSE as can be seen in Table 1. That is, the peak merging makes all probability models
comparable to each other in terms of the position of peaks detected.
4.2. Analysis of entire data

We here applied the proposed peak detection algorithm to the entire data. Before using the
entire data, we removed the uninteresting areas that were produced due to experimental
noise. This can be seen in Supplementary Information Figures S5(a) and S5(b). Then, we
found the nonzero TICs by the proposed NEB model as depicted in Supplementary
Information Figure S5(c). Similarly to the selected data in the previous section, we selected
the nonzero peak regions and then detected the peaks using the proposed methods with the
three cut-off values, 1, 10, and 100, of odds. In case of the cut-off value of odds 10 (1 and
100, respectively), the numbers of detected peaks are 230 (263 and 215), 223 (249 and 211),
225 (254 and 211), 229 (265 and 213), and 215 (230 and 201), for PMM, tGMM, GMM,
GaMM, and EGMM, respectively, before peak merging, while the numbers of detected peak
after peak merging are 97 (104 and 96), 99 (107 and 97), 99 (105 and 96), 99 (106 and 96),
Kim et al. Page 13
and 96 (103 and 92), respectively. As before, the peak merging reduces the variation in the
number of detected peaks among different methods.
We further evaluated the performance of peak finding by compound identification using

Person’s correlation. To standardize the comparison, we focused on the identification of the
76 compound standards from the peak list generated by each method. Since we knew that 76
compound standards should be present in the sample, we examined the quality of detected
peaks by each mixture model through counting the number of 76 compound standards that
were identified out of the detected peaks. Table 2 shows the results of the comparison.
As expected, the odds of one have the most peaks detected for every model. After peak
merging, the total number of detected peaks decreased up to more than 50%, while the
number of unique compounds identified and the number of 76 compound standards
identified have little variation. Interestingly, the difference among models disappears when
we consider the total number of 76 compound standards identified, which ranges from 30 to
32 across all the models.
The trial-and-error optimization was also applied to the entire data using Equation (2.15).
The last three rows of Table 2 show the results of the optimization with the three different
objective functions, MSE, AIC, and BIC. The optimal cut-off values of odds with MSE,
AIC, and BIC are 10, 1, and 1, respectively, which is consistent with the results of the
selected data (Table 1). Since the optimization with either AIC or BIC selects the cut-off
value of one, they detects more peaks than that with MSE. The results are shown in Figure 3
when the objective function is MSE. Overall, the optimization with MSE performs best in
the sense that it finds the smallest number of peaks but the same number of 76 compound
standards. The peak detection results of the trial-and-error optimization using another
replicated data set can be found in the Supplementary Information Figures S7 and S8.
5. Comparison with existing algorithms

We further evaluated the developed algorithm by comparing with existing algorithms in
terms of compound identification. To do this, we employed the two algorithms, continuous
wavelet-based (CWT) algorithm and ChromaTOF. As mentioned earlier, there is no publicly
available software for GC×GC-TOF MS data and most existing algorithms used one-
dimensional approach for denoising and baseline correction, so we employed CWT, which
was the best-performing method based on Yang et al. (2009)’s work. Note that ChromaTOF
is the only commercial software embedded in GC×GC-TOF MS instrument. To avoid bias
in peak merging, we used the peak list generated by each method before peak merging. We
examined the performance of CWT with the three different signal-to-noise (SNR) ratios, 1,
2, and 3, using the R/Bioconductor package MassSpec Wavelet. As for ChromaTOF, we
used the SNR threshold of 100. It should be noted that the unit of the SNR threshold of
ChromaTOF is different from that of CWT, so the SNR thresholds cannot be compared
directly with each other. For example, the CWT detected no peak with SNR of 100.
Table 3 shows the results of compound identification of the entire data using CWT and
ChromaTOF before peak merging. For ease of comparison, we added the results for the
MSE-based trial-and-error optimization of Table 2, which performs best in Section 4.2, into
Kim et al. Page 14
the table and measured the ratios (%) of the number of Standard compounds to the number
of Unique compounds (SUR), the number of Standard compounds to the number of detected
peaks (SPR), and the number of Unique compounds to the number of detected peaks (UPR).
CWT detects the largest number of peaks before compound identification, but it detects the
smallest number of unique compounds as well as the smallest number of the 76 compound
standards (the true positive compounds) identified by compound identification, resulting in
the highest false discovery rate. The commercial software ChromaTOF detects the largest
number of unique compounds and the largest number of 76 compound standards. On the
other hand, although the developed algorithm finds the smallest number of peaks, the
identified number of 76 compound standards is comparable to that of ChromaTOF.
Furthermore, the highest SUR and the highest SPR are achieved by the developed algorithm,
while the highest UPR is carried out by ChromaTOF. It suggests that the developed
algorithm greatly reduces false discovery rate in terms of SPR. In addition, the number of
detected peaks of CWT is very sensitive to the choice of SNR threshold, while the
developed algorithm has little effect of the cut-off value of odds on peak detection as can be
seen in Table 2. Overall, the comparison analysis shows that ChromaTOF has much worse
specificity than our algorithm although it has better sensitivity. Moreover, CWT has the
similar specificity to the developed algorithm, but the developed algorithm has better
sensitivity,
6. Discussion
To analyze GC×GC-TOF MS data, we developed a new peak detection algorithm. Unlike
the existing peak detection algorithms, the proposed algorithm performs baseline correction
and denoising simultaneously using the NEB model without any input, such as manually
assigned SNR threshold and denoising parameters, from users. In particular, the proposed
NEB model has the ability to remove the background noise (the series of black dots in the
middle of the plot) from the raw signal as shown in Supplementary Information Figure
S5(d). Another advantage is that it can reduce the entire data into a set of peak regions using
a statistical test of conditional Bayes factors. This is an important aspect on peak detection
because the information-rich output of MS data is usually enormous and so the processing
time is one of key bottlenecks in data analysis.
In this work, we marginalized the MS information and then detected the peaks using the
marginalized chromatogram data (i.e., TIC). In our proposed peak detection, the
marginalization of the MS data is used only for the peak detection. As for the metabolite
identification, we used the non-marginalized mass spectrum for each metabolite. In the ideal
case, each peak of chromatogram (marginalized MS data, i.e., TIC) should represent a
unique metabolite (compound or peak) in GC×GC-TOF MS data. However, there are still
co-eluting metabolites from GC×GC-TOF MS due to limited separation power. For this
reason, to resolve the co-eluting metabolites, ChromaTOF uses the non-marginalized MS
data (i.e., Single Ion Chromatogram: XIC). A key objective of using XICs of ChromaTOF is
to resolve the co-eluting metabolites, so, if there is no co-eluting peak, we think TIC should
be sufficient to detect the peaks. Furthermore, there is much less amount of metabolites co-
eluting from GC×GC than GC does owing to the increased separation power. For these
Kim et al. Page 15
reasons, we tried to resolve the co-eluting metabolites based on TIC along with a mixture
model in the proposed approach. By doing so, although there is a certain degree of
information loss due to marginalization, we could also see several benefits from this
marginalization: (i) it reduced the size of data, (ii) consequently, it spent the less
computational expense, and (iii) it made the data much smoother (Morris et al., 2005).
Furthermore, in comparison analysis, our approach is comparable with ChromaTOF, which
uses no marginalization of the MS data. It should be noted that neither the commercial
software ChromaTOF nor our developed method completely detected all of the known
compounds. There could be many reasons for this, including low concentration, low
ionization frequency, inaccuracy of the peak detection algorithms, etc.
It is a challenge to estimate the unknown number of components for a mixture model,

especially, under the presence of many local optima. To circumvent this potential issue, the
developed algorithm uses the number of peaks detected by FDT as the upper bound of the
number of components. Although this saves the computation time as well as removes the
potential difficulty, it can be a potential drawback of the proposed algorithm when the true
number of components is larger than the number of peaks detected by FDT. However, since
the FDT used in this study was very sensitive to noise, we observed, with limited testing
data, that FDT overestimates the number of peaks in most cases (e.g., Figure 2).
The most dominated parametric model to describe the shape of chromatographic peaks in
GC-MS and LC-MS data is an exponentially modified Gaussian (EMG) function (Di Marco
and Bombi, 2001). In this work, four mixture models were compared with the EMG model
as can be seen in Tables 1 and 2. EMG model shows the least MSE and the least number of
detected peaks. However, there is no performance difference between the mixture models in
terms of metabolite identification and detected peaks, implying that the less complicated
model has an advantage on the computation.
As mentioned, Table 2 shows no preference among different mixture models on compound

identification, although there is a clear difference in fitting the intensities (Table 1). For this
reason, we analyzed the MS similarity within a peak region displayed in Figure 2(e). The
results of MS similarity analysis are depicted in Supplementary Information Figure S6. In
this analysis, we calculated the pairwise MS similarities among the data points, and then
displayed the pairwise MS similarities for each data point in Figure S6(a). For example, a
dotted line represents the MS similarities between the ith point and all other jth points, j ≠ i,
given the ith data point. Therefore, the ith data point must have the MS similarity of one at
the ith point in the plot since it is the MS self-similarity. In this figure, we can cluster the
MS similarity lines into three groups which are the same as the number of apparent local
maxima. Furthermore, although a data point is located far from its local maximum, its MS
similarity is more than 0.8, demonstrating that the peak region plays a more important role
in compound identification than the peak position. A similar trend can be seen in the
heatmap depicted in Figure S6(b). This can not only explain why we observe no difference
among the different models in compound identification, but also give an insight that MS
similarity-based peak detection is a promising approach.
Kim et al. Page 16
Since the proposed model-based algorithms require a fitting of the peak shape, the peak
finding procedure would run long time. To evaluate the running time, we compared the
computation time between CWT with the cut-off of 1 and the proposed algorithm with/
without optimization with odds of 10, on a desktop with Intel Core 2 Duo CPU 3.00 GHz.
The running time of CWT was 0.24 minutes, while the proposed algorithms with PMM and
optimization took 6.86 minutes and 14.10 minutes, respectively. The full optimization
version of the proposed algorithm further took 33.37 minutes. Although the proposed
algorithms relatively take more running time than CWT, it still finds peaks in a reasonable
time frame. The running time of the full optimization approach may be a bottleneck
compared to CWT, however. One solution to speed up the computation time is to rely on
parallel computation. In general, the parallel computation is more e cient when a lot of
independent calculations are required, and the peak shape fitting of the proposed method can
be performed independently using parallel computation for each of the peak region.
Even though there is not much of a difference between the developed algorithm and the only
commercial software available for GC×GC-TOF MS in terms of the number of 76
compound standards identified, the total number of peaks detected by the proposed
algorithm is about 100 peaks less than that of ChromaTOF (e.g., 230 vs. 391 in Table 3).
This is because ChromaTOF uses XIC, while the developed algorithm uses total ion
chromatogram (TIC). The XIC-based approach requires more computation since it
independently deals with each XIC of m/z values, while the TIC-based approach needs a
one-time computation. The use of XIC on the developed algorithm is left as future work.
7. Conclusions
We developed a novel, publicly-available algorithm to identify chromatogram peaks using
GC×GC-TOF MS data, which includes three components: simultaneous baseline correction
and denoising by the NEB model, peak picking with various choices of mixture models, and
peak merging. The proposed algorithm requires no SNR threshold and denoising parameters
from users to perform baseline correction and denoising. The data analysis demonstrated
that the NEB model-based method can detect the peak regions in the two dimensional
chromatogram that have chromatographic peaks, with a simultaneous baseline removal and
denoising process. Furthermore, the comparison analysis with limited data shows that the
developed algorithm can greatly reduce false discovery rate in terms of compound
identification. Among the model-based approaches for peak picking, PMM and GMM detect
more peaks, while tGMM and EGMM have smaller MSE. However, there is no apparent
preference among the five model-based approaches in terms of compound identification, and
the peak shape is data-dependent. For this reason, we further introduced a trial-and-error
optimization into the proposed algorithm to select a proper peak shape model according to a
different peak region. Among the four measures (MSE, LL, AIC, and BIC), MSE will be
considered to find an optimal peak shape model in terms of the compound identification.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Kim et al. Page 17
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Fig 1.
The graphical representation of a normal-exponential-Bernoulli (NEB) model.
Kim et al. Page 20
Fig 2.
The fitted peak regions and the detected peaks when the cut-off value of odds is 10. The
detected peak positions are indicated by black circle (FDT), red triangle (PMM), green ‘+’
(tGMM), blue ‘×’ (GMM), sky-blue rhombus (GaMM), and purple inverted-triangle
(EGMM). ‘Obs’ means the observed intensities. The detected nonzero peak regions and
peaks before peak merging are in (f). The indices (a)-(e) in (f) indicate the peak region
corresponding to each of the fitted plots (a)-(e).
Kim et al. Page 21
Fig 3.
The detected nonzero peak regions and peaks by the trial-and-error optimization with MSE
before (a)/after (b) peak merging.
Kim et al. Page 22
Table 1
Results of fitting the normalized intensities using five probability models
Odds Measure PMM tGMM GMM GaMM EGMM
1 MSE1 41.34 30.35 28.29 33.85 15.63

(15.03) (19.65) (15.21) (15.92) (9.64)
LL −285.42 −324.10 −322.91 −320.51 −371.78
(41.38) (41.27) (41.66) (41.24) (46.43)
AIC −277.42 −313.76 −312.57 −308.51 −358.92
(40.89) (40.81) (41.21) (40.43) (46.01)
BIC −116.04 −112.24 −111.05 −61.99 −110.92
(18.08) (17.01) (17.42) (18.07) (20.20)
10 MSE 38.34 2.72 6.41 7.39 5.54
(10.52) (0.64) (1.95) (2.52) (2.00)
LL −255.80 −310.07 −305.90 −301.83 −336.24
(39.72) (39.88) (40.63) (39.57) (44.09)
AIC −248.98 −300.51 −296.34 −292.05 −324.98
(39.28) (39.36) (40.11) (38.91) (43.67)

BIC −119.43 −119.40 −115.23 −101.50 −121.72
(18.77) (15.84) (16.56) (17.26) (17.19)
100 MSE 53.75 11.94 19.25 21.05 18.03
(13.52) (7.73) (9.70) (10.54) (9.77)
LL −223.97 −279.79 −277.68 −272.47 −313.56
(36.80) (39.20) (39.85) (37.51) (44.15)
AIC −218.05 −271.12 −269.01 −263.58 −302.60
(36.46) (38.63) (39.30) (36.92) (43.48)
BIC −113.46 −113.01 −112.45 −101.47 −107.04
(18.06) (16.28) (15.65) (14.15) (15.20)
The values in parentheses are empirical standard errors.

Kim et al. Page 23
Table 2
Results of compound identification of peaks detected before/after peak merging
Before peak merging After peak merging

1 2 3
Odds Model Standard Unique Peak Standard Unique Peak
1 PMM 32 72 263 32 64 104
tGMM 32 72 249 32 64 107
GMM 32 72 254 31 63 105
GaMM 32 73 265 31 64 106
EGMM 32 69 230 32 63 103
10 PMM 32 68 230 31 61 97
tGMM 32 70 223 31 62 99
GMM 32 70 225 31 61 99
GaMM 32 71 229 31 63 99
EGMM 32 67 215 32 61 96
100 PMM 31 66 215 30 60 96

tGMM 31 67 211 31 60 97
GMM 31 65 211 30 58 96
GaMM 31 68 213 30 60 96
EGMM 31 64 201 30 58 92
10 4 32 69 230 31 61 97
OPT-MSE
1 OPT-AIC 32 71 255 32 64 104
1 OPT-BIC 32 70 240 32 64 104
1
the number of 76 compound standards present in the list of ‘Unique’ peaks;
2
the number of unique compound names in the list of peaks detected by each method;
3
the number of peaks detected by each method;
4
the trial-and-error optimization.
Kim et al. Page 24
Table 3
Results of compound identification of peaks detected by the developed, algorithm, CWT,
and ChromaTOF before peak merging
Before peak merging

1 2 3
Method (Cut-off) Standard Unique Peak SUR (%) SPR (%) UPR (%)
OPT-MSE (10) 32 69 230 46.38 13.91 30.00

CWT (1) 25 61 1242 40.98 2.01 4.91
CWT (2) 22 50 880 44.00 2.50 5.68
CWT (3) 26 43 618 37.21 2.59 6.96
ChromaTOF (100) 34 178 391 19.1 8.7 45.52
1
Standard/Unique;
2
Standard/Peak;
3
Unique/Peak.
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A new method of peak detection for analysis of comprehensive two-dimensional

Article in The Annals of Applied Statistics · August 2014

Seongho Kim Ming Ouyang

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Jaesik Jeong Changyu Shen

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Ann Appl Stat. 2014 June ; 8(2): 1209–1231.

A NEW METHOD OF PEAK DETECTION FOR ANALYSIS OF

Changyu Shen, and

Wayne State University, University of Massachusetts Boston, Chonnam National University,

(NEB) model; peak detection

Metabolites analyzed on a GC×GC-TOF MS system are first separated on two-dimensional

is in general computationally extensive. Yang et al. (2009) compared the performance of

To avoid the aforementioned difficulties in analysis of GC×GC-TOF MS data, we propose a

analysis of GC×GC-TOF MS data. To address this, we employed five probability mixture

2.1. Finding peak regions

Therefore, the marginal density of Xi when i ≠ 0 is driven by

graphical representation of the proposed NEB model is depicted in Figure 1.

Parameter estimation—The EM algorithm (Dempster, Laird, and Rubin, 1977) is

computation as well as to enable a nice interpretation of the output, according to Newton et

The posterior probability of yi given the entire TIC is

2.2. Denoising and baseline correction

2.3. Peak detection and area calculation

Model-based approach—The five different probability models including Poisson,

, a mixture of the selected probability models are fitted to the observed,

2.4. Peak grouping and merging

where ; are the parameter

3. GC×GC-MS data and software

set generated from a comprehensive two-dimensional gas chromatography time-of-flight

(CWT) algorithm and ChromaTOF, in terms of compound identification in Section 5.

4.1. Analysis of selected data

4.2. Analysis of entire data

We further evaluated the performance of peak finding by compound identification using

5. Comparison with existing algorithms

It is a challenge to estimate the unknown number of components for a mixture model,

As mentioned, Table 2 shows no preference among different mixture models on compound

dimensional gas chromatography/time-of-flight mass spectrometry. Analytical Chemistry. 2011;

Pierce K, Wood L, Wright B, Synovec R. A comprehensive two-dimensional retention time alignment

Odds Measure PMM tGMM GMM GaMM EGMM

1 MSE1 41.34 30.35 28.29 33.85 15.63

(39.28) (39.36) (40.11) (38.91) (43.67)

The values in parentheses are empirical standard errors.

Before peak merging After peak merging

100 PMM 31 66 215 30 60 96

Before peak merging

OPT-MSE (10) 32 69 230 46.38 13.91 30.00

ChromaTOF (100) 34 178 391 19.1 8.7 45.52

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