Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220

Contents lists available at ScienceDirect

Chemometrics and Intelligent Laboratory Systems

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c h e m o l a b

Review

An introduction to Bayesian methods for analyzing chemistry data

Part II: A review of applications of Bayesian methods in chemistry
D.B. Hibbert ⁎, N. Armstrong
School of Chemistry, University of New South Wales, Sydney NSW 2052, Australia

a r t i c l e i n f o a b s t r a c t

Article history: A critical literature review with 207 references is presented on the use of Bayes theorem in chemistry.
Received 30 June 2008 Discussion is grouped into areas of application, including general chemistry, chromatography and mass
Revised 27 January 2009 spectrometry, spectroscopy, microbiology, and metrology in chemistry and environmental chemistry.
Accepted 4 March 2009
Reference to methodology is given to Part I of this series. Recurring themes throughout chemistry are
Available online 2 April 2009
parameter estimation (often using marginalization), joint distributions calculated by Markov Chain Monte
Carlo methods, Bayesian classification, Bayesian regularized artificial neural networks, and the use of
Keywords:
Bayesian analysis
Bayesian priors to incorporate expert knowledge.
Chemistry data analysis © 2009 Elsevier B.V. All rights reserved.
Chemometrics and statistics
Forensic sciences and medical testing
Model selection
Parameter estimation

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
2. Analytical and general chemistry applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
3. Chemometrics and statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
4. Forensic sciences and medical testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
5. Microbiology and DNA analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
6. Chromatography and mass spectrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
7. Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
8. Metrology in chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
9. Environmental chemistry and occupational health and safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
10. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

1. Introduction according to the fields of use in the chemical sciences. A particular

Bayes theorem was derived not only for the use of chemists, and
examples can be found in all fields of science, many of which overlap
chemistry. A search on the keyword “Bayes” in Current Contents
reveals more than 250,000 hits in the physical and biological sciences.
Within chemistry the authors have found around 800 substantive
references, and more than 200 are given here. General references to
Bayes theorem from the statistical literature can be found in our first
paper [1] and later in this section. The paper is divided into sections
technique might therefore recur throughout the paper.
In terms of Bayes theorem recurring themes throughout chemistry
are parameter estimation (often using marginalization), joint dis-
tributions calculated by MCMC1 methods, classification, BRANNs, and
the use of Bayesian priors to incorporate expert knowledge. Some of
these techniques are covered in Part 1 of this tutorial [1] and a brief
description will be given where they are first referenced in the present
text.

1
⁎ Corresponding author. Because of the numbers of acronyms and abbreviations not all terms are expanded
E-mail address: b.hibbert@unsw.edu.au (D.B. Hibbert). in the text, but a glossary is provided.

0169-7439/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.chemolab.2009.03.009
212 D.B. Hibbert, N. Armstrong / Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220
For interested readings a review of applications in Physics may be
found in Reports in Progress in Physics [2]. D'Agostini [3] also gives a
good review of Bayesian methods from a physics' viewpoint. An
unlikely review of Bayesian theory is given by Blasco in the context of
quality testing of meat [4], and there is a book on Bayes theorem in
archaeology [5]. Three general books that can be recommended are by
Sivia and Skilling [6], Bolstad [7] and Gregory [8]. Other texts which
may interest the reader are: Gelman et al. [9], Gamerman and Loes
[10], MacKay [11]. These provide up to date discussion and application
of Bayesian analysis.
We have tried to avoid the frequentist versus probabilistic debate,
or that between the subjective Bayesians and the objective Bayesians,
but for general reading on these discussions see Howson and Urbach's
Nature contribution from 1991 [12], Efron's “Why isn’t everyone a
Bayesian?” [13] or Brooks [14].
2. Analytical and general chemistry applications
A typical classification employing Bayesian modeling is reported
by Blanco-Gomis. The amino acid and riboflavin contents of apple
juices clarified by microfiltration and ultrafiltration were measured by
HPLC and then classified by a number of multivariate methods [15].
Bayes classification performed well, but had a 22% Type II (β) error
rate. In another study, alcoholic distillates were classified from GC data
[16], and, also from Spain, a classification of cider brandy [17]. A Bayes
critical function established on the basis of multiple-linear-regression
characteristic vectors obtained from the first and second derivatives of
the NIR spectra (680–1235 nm) of a training set of 205 fresh silk worm
cocoons gave a success rate of 95.7% in distinguishing between male,
female and dead silkworms in a sample set of 375 cocoons [18].
Some problems with neural networks that can be addressed in a
Bayesian framework include deciding the optimal complexity of the
model, and obtaining appropriate confidence intervals on the results
[19]. Given inputs x and outputs y into a multilayer perceptron (MLP)
with transformation function D governed by model parameters (e.g.
hidden layer weights and biases) and hyperparameters which are
contained in θ, the posterior distribution can be integrated with
respect to θ,
R 2
P ðyjx; DÞ = P ðyjx; θÞP ðθjDÞdθ
and the likelihood part is given by Bayes theorem,
P ðθ jDÞ~P ðDjθÞP ðθÞ:
In a MCMC solution, the integrals in the marginalization are
calculated by drawing samples from the joint probability distribution
of θ. The predicted y is then the expectation of the posterior
distribution in Eq. (1).
Because many of the integrations in Bayesian analysis have no
simple algebraic solution, numerical methods using the Markov
Chain Monte Carlo algorithm are often used. A Markov chain is a
series, which has the property that given the present state, preceding
and following states are independent, and Monte Carlo relates to a
random process. Thus, each iterate uses knowledge of the preceding
values, for example constraints on the likelihood can guide the step
size and direction. Many computer programs implement the MCMC
algorithm; at the time of writing WinBugs is particularly popular (see
http://www.mrc-bsu.cam.ac.uk/bugs/winbugs).
Bayesian regularized artificial neural networks (BRANNs) have
been reported by the de Valle group to classify substances ‘tasted’ by
an electronic tongue, including amino acids [20], ammonium and
alkali metal ions [21–23], and nitrate [24]. The BRANN algorithm has
the advantage that it avoids overfitting without the need to monitor
the fitness of an internal validation subset. A spectrophotometric
analysis of salicylic acid using copper also employs BRANNs [25].
Another Spanish study which compared many classification methods
(including Bayesian) involved Galician honey [26].
Roussel et al. have described what they call “Bayesian fusion of
inferences” from aroma tests, FTIR and UV on the origin of wine musts
[27]. Both the maximization of posterior probability and the
minimization of risk (cost of failure) are investigated.
In situations where the classification requires high level of
human (non-statistical) input, inductive learning algorithms such
as C4.5 outperform multivariate and probabilistic models, although
the provision of a probability of the classification was considered a
strength of the Bayesian method [28–30]. This is shown for classi-
fication based on noisy elemental measurements by ICP AES and
ICP-MS, of reference compounds [28], geological samples [30], and
of alloys [29].
In process monitoring, an iterative Bayesian approach has been
developed for the inverse problem of optimizing output given flow
data from a number of units [31]. For the case of Gaussian random
variables the solution reduces to an iterative weighted least squares
approach amenable to online implementation, with a weighting
derived from the Bayesian prior. The example reported is a ‘Sulfreen’
unit in a refinery, where concentrations of H2S and SO2 are measured
by a number of parallel input analyzers before their combination and
reaction. As with many of the problems solved by Bayesian approaches
this is an inverse problem in which the measured concentration
profile at some outlet point (F) must be deconvoluted to give
concentrations at different units in the plant (f), and some
transformation matrix (M),
F = Mf + e ð3Þ
where ɛ is an error matrix.
Using the BIC, the optimal set of Gaussians and their parameters
can be determined for process control models [32]. Note that the BIC is
often called the Schwartz Information Criteria (SIC) [33] and is
approximate version of a full Bayesian approach. Schwarz showed that
an optimum model is one that maximizes,
kj
log Lj − log n ð4Þ
ð1Þ
where Lj is the value of the maximum likelihood function for model j
of dimension kj, for n observations. Schwarz drew on, and improved
the Akaike information function [34] for which the second term was
ð2Þ simply kj.
Food quality testing, and inferences on shelf life of yogurt were
treated by a Bayesian method in which priors from tests on fat-free
yogurt were used in an analysis of full fat products [35]. The likelihood
was taken as a Weibull distribution, which is commonly used to model
product failure.
There have been a few examples of Bayesian analysis applied to
electrochemical results, mostly from Fahidy who predicts electro-
chemical parameters and their probabilities from an assumed
Gaussian (or Student t, for small sample size) distribution [36,37].
The conditional probabilities for the presence of molecular
skeletons of sesquiterpene lactones in a given taxon was computed
using botanic information as input by Emerenciano et al. [38].
Particle size distributions can be calculated from light sensor data
by simulating the distribution and using Bayes theorem to predict the
hit probability for each particle diameter [39]. An iterative procedure
then matches the simulated and observed results.
3. Chemometrics and statistics
An early paper illustrating so-called ‘empirical’ Bayes methods for
parameter estimation was published in this journal in 1992 [40]. The
method introduces a hyperparameter (λ) that is estimated from the
 D.B. Hibbert, N. Armstrong / Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220
data, and represents a family of prior distributions. This distinguishes
the method from pure Bayesian models that have single priors and
classical methods that have unspecified priors.
Analysis by UV–vis spectrophotometry was interpreted by a
Bayesian method, which generates estimates of the concentrations
of the components of an analyzed substance on the basis of the data
representative of its absorption spectrum [41]. A requirement was that
both the normalized spectra of the components and statistical
information on historical measurements of the monitored concentra-
tions were available.
Reduction of dimensionality in spectroscopy or chromatography
can be achieved by sequential projection pursuit with the use of
Bayesian criteria for choosing numbers of factors [42]. Brown et al.
have reported Bayesian selection of features [43] and classification of
NIR and mass spectra after reduction in dimensionality by wavelet
transformation [44].
The problem of distribution of compounds in highly diluted
solutions is of importance in molecular biology, environmental and
geochemistry. Vlad et al. [45] derive distributions of the Dirichlet type
from a consideration of probability density functions of the different
species.
Bayesian information criteria have been used to choose wavelets
from NIR in the unsupervised classification of spectra and is described
by Donald et al. [46]. A multivariate Bayesian approach to visualizing
IR data of traditional Chinese medicines has been reported by Cheng
et al. [47], and a Bayesian principal components analysis, which
incorporates prior knowledge about the data and model, by Nounou et
al. [48]. The parameters of a PCA model are the projection cosines (α),
the principal components (Z) and the rank of the model, p. A Bayesian
posterior then gives the credibility of these parameters as a function of
the data (X),
P ðZ; α; p jXÞ~P ðXjZ; α; pÞP ðZ; α; pÞ:
If the rank has been estimated, p can be removed from the posterior,
and the remaining parameters are estimated using an empirical
Bayesian method.
A fundamental exposition on Bayesian latent response models is
given by Dunson et al. [49]. A MCMC algorithm is proposed for
posterior computation. An empirical Bayes approach to fitting a factor
analysis model of aerosol masses is given by Gleser and Yang [50]. The
model provides reasonable two point estimators for the vectors of
source contributions and their accuracy is established using simulta-
neous confidence intervals.
From the world of currency forecasting comes a genetic algorithm
approach to synthesize a Bayesian belief net from an arbitrary stream
of temporal data. With the interest in genetic algorithms in chemistry
this might be a useful approach to investigate [51].
A general discussion of Bayesian classification of multicollinear
data in chemistry is given by Naes and Indahl [52]. Discriminant
methods of supervised classification such as linear or quadratic
discriminant analysis are Bayesian in nature. The prior probability of
membership of a group can be taken from the frequency of member-
ship of that group in the training set. An unknown sample is allocated
to the group j with the smallest value of Cj,
 T  
−1
Cj = xi −μ j Σj xi − μ j + log jΣj j − 2 log πj
where μj is the mean of group j, and Σj the corresponding covariance
matrix. The approach is unified with Fisher's canonical discriminant
analysis through the covariance matrix.
A classification technique that combines the recursive partitioning
feature of tree-based classifiers (e.g. classification and regression
trees) with the probabilistic reasoning of Bayesian networks is
described by Mello and Brown [53]. The classification of FTIR spectra
for the presence or absence of alcohols based on a principal
213
components analysis was reported by Perkins et al. in 1992 [54]
using Bayes discrimination. Bayes discrimination based on a combina-
tion of a radial basis function and partial least squares has been
proposed for pattern classification [55]. Shu et al. tackle this problem
in terms of Bayesian regularized networks [56]. A Bayesian discrimi-
nation algorithm for classifying IR spectra had been proposed by
Woodruff et al. in 1974 [57]. A multivariate Bayesian discriminator for
classifying spearmint essence is also reported [58]. Bayesian classifi-
cation on a PCA subspace is proposed for use in fault detection in
process control [59]. In this method, the score vectors are classified by
solving the Bayesian classification problem with the deterministic
annealing expectation maximization and robust mixture decomposi-
tion algorithms. This approach to classification, called by Liu et al.
“Bayesian clustering with variable selection” is explained in detail in
[60].
Missing data in training sets for neural network classifiers is
treated as a probabilistic problem by Woody and Brown [61] who use
their PLS-Bayes hybrid classifier to show robustness against such
missing data [62]. For a general review of Bayesian neural networks
see [63].
The relevance vector machine for pattern recognition is described
by Bishop and Tipping [64] in a paper in the NATO workshop series. It
is claimed that the Bayesian approach leads to improved classification
over the more usual support vector machines.
The Moscow group led by Pomerantsev has developed a novel
method for non-linear regression known as sequential Bayesian
regression (SBE) [65]. The method processes the data successively for
every response with information about common parameters being
passed on at each stage. Parameter estimates are simulated in the
calculation of confidence intervals, (unlike bootstrap methods that
estimate initial data). The method has the same accuracy as bootstrap
but is about 1000 times faster. SBE is used to estimate kinetic
ð5Þ parameters from evolving spectral data [66]. Their software (Fitter) is
available as an Excel Add-in. An earlier paper by the group uses a
Bayesian approach to predict the aging of polymers [67].
Joergensen and Pedersen presented a Bayesian approach, which
utilizes the Metropolis algorithm, for calculating the distribution of
parameter values associated with a specific physical model and a
particular data set [68]. The method can automatically adjust the
sampling space to the optimal size. A different approach to kinetic
analysis with variable temperature during a run uses genetic
algorithms and pruning computational neural networks to select the
number of inputs required to correct the temperature variations [69].
The genetic algorithm uses a pruning procedure based on Bayesian
regularization and is highly efficient as a feature selector providing
good results in the generalization process without the need to use a
validation set.
Experimental design using Bayesian priors has been proposed by
Atkinson and Bogacka [70] for determining kinetic orders of reaction.
Chaloner and Verdinelli give a general review of Bayesian experi-
mental design [71], and Sivia devotes a chapter to experimental design
in his excellent book on Bayesian analysis [72].
Selection of an appropriate and suitably parsimonious model
among alternatives has been discussed in a Bayesian framework, most
recently by Armstrong [73] for HPLC (see below), and in engineering
by Beck and Yuen [74]. The problem can be reduced to one of
ð6Þ parameter estimation as shown in the context of perturbed angular
correlation of gamma-rays [75], or can be considered from the point of
view of logic [76]. Dose [2] also highlights the model selection
problem in his review.
4. Forensic sciences and medical testing
The ability of Bayes Theorem to draw on a wide range of
information to estimate a posterior probability has been used by
Sagalovsky et al. [77] to locate illicit substances in sealed containers,
214 D.B. Hibbert, N. Armstrong / Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220
using a non-destructive test and other information. It is suggested that
X-ray measurements, fast-neutron transmission measurements, cargo
manifest data and, possibly, information of a physical, chemical or
even psychological nature can be used. The paper shows how fast-
neutron and X-ray data can be manipulated in a generalized least
squares method to compute the posterior probability distribution.
They state, “An advantage of the Bayesian approach is that the effects
of any erroneous initial assumptions with large, uncorrelated
uncertainties are soon overwhelmed by accumulated objective data”.
The major impact of Bayes Theorem in the forensic sciences in
recent years has been in DNA testing, but the idea of providing the
court with a probability of an event is older. Indeed the courts regard
a statistician giving the probability of the guilt or innocence of a
defendant as a complete anathema. The case of R v Adams in the UK
established that to use Bayes Theorem or similar method in a criminal
trial to bring together probabilities of the ultimate issue (the guilt or
innocence of the defendant) “plunges the jury into inappropriate and
unnecessary realms of theory and complexity deflecting them from
their proper task” [78,79]. The ‘prosecutor's fallacy’, which is based on
the ‘fallacy of the transposed conditional’, confuses the difference
between the probability of finding evidence given the truth of the
hypothesis (the guilt of the defendant) and the probability of the
hypothesis given the evidence [80]. Forensic scientists are trained to
explain to the court the likelihood of the evidence, and to stay away
from any suggestion of the guilt or innocence of the defendant. Thus a
statement such as ‘The odds that the DNA found at the crime scene
came from an unrelated (to the defendant) white male are a million to
one against.’, will be made; but not ‘The chance that the defendant
was at the crime scene is a million to one on.’, or even worse ‘The odds
that the defendant is innocent is a million to one against.’ Further
discussion on this point can be read in works by Taroni and co-
workers [81–83], and Buckleton et al. [84]. A critique of the use of
equal prior probabilities, needed to establish a posterior probability
from the likelihood, has recently been made by Biedermann et al. [85].
Analysis of dyes in illicit amphetamine tablets by TLC and CZE is
reported by Goldmann et al. [86], and the incorporation of this
information into a strategic view of distribution of drugs can be done
using Bayes theorem. This group has also discussed the evaluation of
links in heroin seizures within a Bayesian framework [87]. Although
not chemistry, the Bayesian analysis of the probability of a wife beater
actually killing his wife with reference to the O J Simpson trial of 1994
is an interesting example of use and misuse of statistics [88]. See also
Part I of this tutorial [1]. Bayesian networks can also be used to assess
evidence as discussed by Garbolino and Taroni [89] and Taroni et al.
[90].
Coulson et al. give an example of application of Bayes theorem to
sampling seized tablets [91]. The problem is stated as given a seizure
of a large number of tablets from an alleged clandestine laboratory,
how many should be analyzed to conclude with reasonable prob-
ability that a certain amount of drugs was present? The likelihood is
the hypergeometric distribution and non-uniform priors are used,
based on the experience of forensic analysts, that give weight to
identical pills all containing drugs, or all not containing drugs. The
approach tends to offer considerably fewer tablets to be analyzed
than, for example, the UN guidelines. This is a good example of using
entirely appropriate prior knowledge that does indeed distinguish
among different hypotheses.
The distributions of nandralone metabolites from amateur and
professional football players was reported by Robinson et al. [92] in a
Bayesian analysis in which the posterior distribution was obtained via
odds ratios calculated from a 2 × 2 contingency table.
Toxicology data for a number of drugs was analyzed to see if the
identity of an ingested drug could be inferred from observations of
symptoms. Using Bayesian methodology it was shown that the
identification depended largely on the prior probability of what
drugs were available to the patient. Therefore identification has to
stem from local knowledge rather than some universal set of
symptoms [93].
The kind of decision found in forensics, guilty/not guilty, is
mirrored in medical testing when the presence or absence of a disease
is the outcome of interpretation of a chemical test (see for example
[94]).
5. Microbiology and DNA analysis
We have already seen examples of Bayesian probabilities being
used to make correct statements about matching DNA samples for
forensic purposes, but there is considerable literature on the general
problem of description (identification, matching, structure and
sequencing) of DNA, proteins and other biological molecules
based, often, on mass spectrometric analysis. Beaumont and Rannala
in 2004 give a useful overview of the rise of Bayesian statistics in
genetics [95], citing a pragmatic, rather than philosophical, reason. It
is only with the advent of sufficient computing power, coupled with
the appropriate algorithms, that joint distributions can be deter-
mined using MCMC techniques. This echoed a similar discussion
concerning medical statistics published in the British Medical
Journal in 1998 [96]. An example of Bayesian priors in a gene
expression experiment is given by Long et al. [97]. The Bayesian prior
allows statistical inference to be made from microarray data even
when experiments are only replicated at nominal levels. Statistical
tests based on analysis of variance and a Bayesian prior identify
genes that are up- or down-regulated following experimental
manipulation more reliably than approaches based only on a t test
or fold change. Gene expression-based tumor classification, includ-
ing Bayesian methods, is reviewed in a paper in 2001 [98], now
somewhat out of date. Another example from analysis of biological
systems comes from two dimensional GCMS of urine from two
inbred populations of mice [99]. Bayesian analysis was used to
identify the mice with the gene for expression of the major
histocompatibility complex.
Quantitative Structure Activity Relationships (QSAR) epitomize
soft modeling approaches. Burden and Winkler have shown that in
fitting data with a weighted penalty function using neural networks,
Bayes theorem can be used to obtain the distributions of weighting
parameters and thus optimize the prediction of the network [100–
102]. They have demonstrated models for physiochemical properties,
drug targets and blood-brain permeability. Aromas of 133 derivatives
of pyrazine were modeled by molecular descriptors in a Bayesian
neural network [103].
Protein identification from extracts of cells is the first step in
proteomics research. Large databases have been created from LC–MS
and LC–MS/MS data. Identification of many hundreds of proteins from
a cell culture is now possible. Chen et al. [104] show that simple m/z
and retention information, coupled with a Bayesian classifier that
models the distributions of parameters as Gaussian can lead to
improved identification. A more complex approach using (inter alia)
Bayesian scoring for neural networks has been published by Lokov et
al. [105], and Zhang and Chaite have reported a Bayesian search
algorithm (Pro-found) [106]. Yanofsky et al. has made a Bayesian
analysis of errors in masses in LC–FTICR–MS [107], as part of a better
understanding of identification of proteins. Identifying a particular
protein from a database, given a number of database search scores
obtained from structural or experimental observations can be couched
in terms of Bayes theorem with joint probability distributions [108],
P ðx1 N xn j + ÞP ð + Þ
P ð + jx1 N xn Þ = ð7Þ
P ðx1 N xn j + ÞP ð + Þ + P ðx1 N xn j −ÞP ð −Þ
where xi is a database search score for the ith assignment, and + or −
indicate a correct or incorrect assignment. The joint distributions can
be investigated using MCMC techniques or combined in some overall
 D.B. Hibbert, N. Armstrong / Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220
figure of merit. Keller et al. [108] use linear discriminant analysis to
combine the scores xi into a single function.
X oxidation of glucose. The theory of ‘mixture of experts’, a Bayesian
F ðx1 N xn Þ = a + bi xi :
i current, blood glucose value at the calibration point, and a calibrated
Sadygov et al. [109] has treated the identification of a protein from
tandem mass spectra peptide fragment data as a Bernoulli event. Their
multinomial model combines the database search results and
generates an observed frequency distribution of cross-correlation
scores (grouped into bins) between experimental spectra and
identified amino acid sequences. A protein identification probability
is the multinomial probability of observing the given set of peptide
scores.
At the level of elucidation of secondary protein structures, Liu's
group has published a thorough exposition on the problem and a
Bayesian approach to its solution [110]. For a given protein of known
sequence of amino acids, each position must be classified as part of an
α-helix (H), extended β-strand (E) or a loop-coil (L). A protein is
described in terms of amino acid residues, R which in turn are
characterized by structural segments S with defined starting amino
acid m and secondary structure classification T. A joint distribution is
defined
jY
=m  
P ðR; m; S; T Þ = P ðm; S; T Þ P R½S  jm; S; T
j−1 + 1 :Sj
j=1
The joint likelihood can be marginalized over the latent variables S
and T. A special case of Eq. (9) is a hidden Markov model. MCMC is
used to overcome the near impossibility of evaluating probabilities
over all possible segment interactions. Further details are given in
[110] and other publications from this group. The similar problem of
RNA secondary structure obtained from a knowledge of the ribonu-
cleotide (A, C, G or U) sequence and stacking energy calculations is
treated by Ding and Lawrence [111]. The search is analogous to
dynamic programming algorithms, and recursively builds on all
penta-nucleotide fragments. The binding of water molecules at
specific sites in a protein, and their possible displacement by drug
molecules, has been assessed by a Bayesian approach [112].
X-ray crystallography of proteins also draws on Bayes theorem to
obtain information from electron density maps and other ‘scenes’
[113].
At the higher level of gene sequencing, hidden Markov models
(HMM) are described by Liu and Logvinenko [114]. An approach using
HMM for sequence alignment was used by Mitchison [115].
The Bayesian design criterion of the expected information content
of an experiment was used by Merle and Mentre to decide optimum
sampling in a pharmokinetic study of an anti-depressant drug [116].
Mahmood has reported a similar study on renal patients and
concluded that Bayesian sampling was superior to the more
traditional ‘truncated area’ method [117], and Bennett et al. also
used Bayesian sampling in a study of bismuth uptake [118].
Classification of kinase inhibitors based on chemical features was
demonstrated using a Bayesian classifier by Xia et al. [119]. He used
Laplacian weighting to correct for features that appeared with low
frequency in the 200,000 compound database. An early work in this
area comes from 1985 in a study that predicted pharmokinetic data
based on drug assays [120].
Microbiological assays commonly use incubations of multiple
tubes in a dilution series, and microorganism concentration is read as
a most probable number (MPN) in standard tables for the observed
pattern of positive tubes. The available tables differ and McBride et al.
have shown a Bayesian analysis with Poisson distributed priors gives
defensible credible intervals on the values of MPN [121].
215
Non-invasive glucose analysis by the “Gluco Watch” measures
hydrogen peroxide in a hydrogel on the skin from the enzymatic
ð8Þ technique, applied here uses inputs of elapsed time, integrated
signal [122]. The output was the value of blood glucose at each
measurement. In the mixture of experts method the output A (here
blood glucose concentration) is given by the sum of values from
‘experts’, the number of which, n, can be determined in an
optimization, multiplied by a weighting factor.
2 ! 3
Pm
0 1
6 exp α i;j P j + fi 7
Xn 6 j=1 X
m 7
A= 6 ! @ a P + z A7 ð10Þ
6 n i; j j i 7
i=1 4 P P 5
m
j=1
exp α i;j Pj + fi
j=1 j=1
ai,j, αi,j and zi and ζi are parameters of the model, and Pj is a measured
quantity. In the glucose example there are n = 3 experts and m = 4
measured quantities, therefore there are 30 parameters. Although the
method has similarities to neural networks it is computationally
simpler and it is possible to display the contribution of each expert,
allow better interpretation of the model.
6. Chromatography and mass spectrometry
ð9Þ
The earliest report of Bayes theorem applied to chromatography
comes from Kelly and Harris in the 1970s who showed that
maximizing the posterior probability allowed better estimation of
peak parameters in gas chromatography [123]. Peak resolution of
doublets using priors that recognized that the height of the second
peak must be greater than zero followed [124]. A use of Bayes
Theorem from 1986, to go from a probability density of an event given
a particular hypothesis to the probability of the hypothesis is an
investigation of the number of resolvable peaks of a chromatogram
given knowledge of the peak width and peak capacity [125]. The
problem is similar in form to that of the number of pills problem
discussed above. It is possible to calculate the probability of separating
out (at baseline or peak) p peaks from a possible m given a peak
capacity n. However experimentally the number of components in the
sample is unknown, the analyst can only count the number of peaks
separated in the chromatogram. The problem is thus: after having
observed p peaks at a given peak capacity, n, what is the probability
distribution of the number of components in the sample P(m|p, n)? A
flat prior was chosen reflecting the a priori lack of knowledge about
the number of components, and thus the probability, with an
assumption of flat priors is
P ðp jm; nÞ
P ðmjp; nÞ = P ð11Þ
P ðp jm; nÞ
m = 1;∞
Martin et al. showed that for reasonably complex mixtures it is
very unlikely to obtain complete resolution using an un-optimized
system [125]. For example, the probability of resolving 10 peaks on a
column with capacity 50 is only 20%.
Models of band broadening in chromatography have been assessed
using Bayes theorem [73], which was proposed as an alternative to
orthodox statistical techniques for quantifying the parameter values in
the models. It is then possible to test the statistical plausibility of
competing models, which enabled the models to be ranked in an
ordered manner.
The problem of determining the composition of a gas mixture
from its low-resolution mass spectrum has been addressed by the
group of Preuss [126,127]. The noise is modeled in an expression for
216 D.B. Hibbert, N. Armstrong / Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220
the vector of signals from mass channels (d) in terms of the cracking
matrix C, concentration vector x and error vector ɛ, (he2n i = s2n )
d = Cx + e
from which the likelihood of d is
! 
Y 
2 −1=2 1 T −2
P ðdj x; C; SÞ = 2πsn exp − ðd −CxÞ S ðd − CxÞ ð13Þ
2
n A Bayesian classifier performed better than a maximum likelihood
and S− 2 is a diagonal matrix with elements 1/s2n. Prior probabilities of
x are taken as flat in an appropriate range of sensible concentrations.
The posterior probability for x and C are obtained after some algebra
and MCMC evaluation of integrals.
Meier and Marshall show that Bayesian estimates of ion cyclotron
resonance peaks are better than Fourier Transform when the data is
discrete, truncated and noisy [128,129].
The assignment of complex mass spectra is a discrete deconvolu-
tion problem (see next section). Karrer et al. have shown that a
Bayesian approach is statistically more sound than the traditional least
squares techniques for determining amount-of-substance fraction
[130].
7. Spectroscopy
The most fundamental problem in spectroscopy, which covers
many aspects of science, is the determination of the frequency of a
phenomenon from time data (The lengths of the year or lunar month
from observations of the heavens are perhaps the oldest non-
spectroscopic problems). Bretthorst has made his PhD thesis, first
published by Springer, available on the web [131]. It contains a good
introduction to Bayesian methods for spectral analysis and parameter
estimation.
Stoyanova et al. published a method based on MCMC for the
deconvolution of spectra, so-called Bayesian Spectral Deconvolution
(BSD) [132,133]. Applied to the massive amounts of data from NMR
chemical shift images (typically 512 spectra each of 512 points), their
method allows decomposition of the data matrix into component
spectra and a mixing matrix together with confidence intervals.
MCMC is used to probe distributions with atomic priors that reflect
the known sharpness of peaks in NMR. The application of BSD is
illustrated by 1H NMR urine spectra from rats treated with different
doses of hydrazine. Eighteen spectra were identified with BSD that
were related to the unaltered and “aberrant” urine patterns [133].
Other work relating to NMR includes Whittenburg's use of Bayesian
methods to remove baseline roll [134] and solvent peaks [135].
Bayesian statistics were applied to the estimation frequencies and
amplitudes of NMR free induction decay signals by Evila et al. [136]
with improvements over the usual Fourier Transform methods, and
this theme was taken up again by Ebbels et al. in 2001 [137]. See also
[128,129,138]. Rotational anisotropy in NMR spectra of proteins can be
distinguished from chemical exchange, and quantified using a
Bayesian Monte Carlo approach [139]. Spectral deconvolution of
reflectance data from blends of steam coal is reported by Lester et al.
[140].
Deconvolution of spectra has used Bayesian approaches as
reported in a number of papers, with much of the early work coming
from the nuclear physics community [141–146]. Recently deconvolu-
tion of a mixed spectrum using Bayesian MCMC methods has been
reported [147]. In elastic recoil detection analysis the measured
energy spectra suffers from broadening due to energy straggling,
multiple and plural scattering, and surface roughness. Broadening and
measurement error leads to a difficult deconvolution problem
associated with the determination of the depth profiles from the
energy spectra, involving solution of degenerate systems of equations.
Erdelmann et al. reported a Bayesian method for deconvolution using
Monte Carlo to simulate the measurement process [148]. Other work
ð12Þ
on depth profiling concerns ion beam experiments [149], Rutherford
back scattering [150,151] and nuclear microprobe experiments [152].
An early example of deconvolution involved PIXE spectra from
amniotic fluids that were deconvoluted using a programmed Bayesian
method [153].
 Deconvolution of ICP-MS spectra by a Bayesian approach as a
prelude to calibration is reported by Sharp et al. [154,155].
or simplex learning machine for classifying chemical features of nearly
4000 13C spectra provided by the USEPA [156]. A spectrum was coded
as a 256-bit binary string at 1-ppm intervals, and the increase in the
information before and after classification was used as the optimized
criterion.
X-ray methods have been treated by Bayesian methods. Arm-
strong et al. reported a single-step, self-contained method for
determining the crystallite-size distribution and shape from experi-
mental X-ray line profile data [157]. It was shown that the crystallite-
size distribution could be determined without invoking a functional
form for the size distribution, determining instead the size
distribution with the least assumptions by applying the Bayesian
maximum entropy method. X-ray spectra analyzed by a fuzzy neural
network system have elements identified by computation of
conditional a posteriori Bayes probabilities in work by Walczak
et al. [158].
Spectral image analysis with a Bayesian constraint has been
combined with an ALS algorithm for analysis of multivariate or
hyperspectral data [159]. Bayesian discriminant clustering of the
intensity sub-matrix amounts to a spatial constraint, because the
probability of class association is used as a way of limiting the
components that are allowed to appear in a given pixel. The approach
is a modification of so-called modified alternating least squares (MALS)
concept.
Gaussian process regression develops linear and non-linear
calibration models within a Bayesian probabilistic framework. Chen
et al. show how this can be implemented in a MCMC method for NIR
analyses of two systems; the active pharmaceutical in a set of tablets;
and moisture, fat and protein content of meat samples [160]. The
paper is critically discussed by Sha [161], and Brown [162] and
responded to by the authors [163].
8. Metrology in chemistry
Measurement uncertainty and the approach given in the “Guide to
the Expression of Uncertainty in Measurement” (GUM) is inherently
Bayesian [164,165], and in its evolution it will become more explicitly so
[166]. When an expanded uncertainty is quoted as “… an interval
containing approximately 95% of the distribution of values” this is no
longer a frequentist description of the range that would encompass a
fraction of repeated experiments, but a characterization of the
probability density function of the measurand. The Bayesian approach
is typified in “Type B uncertainties” and leads to probabilities that
describe belief in the location of an unknown parameter within a defined
distribution [167]. Lira and Wöger [168,169] address the problem of
evaluating the uncertainty in knowing a quantity measured directly with
a measuring instrument. It is shown that, under some conditions, the
uncertainty associated with the uncorrected result can be obtained from
that associated with the correction. In later work they develop an
explicitly Bayesian model of measurement uncertainty and conclude
that the application of Bayes theorem leads to an improved method for
evaluation of uncertainty, particularly in the case of the coverage
probability [170]. In a contribution from NIST the use of prior
information can reduce the expanded uncertainty of a measurement
 D.B. Hibbert, N. Armstrong / Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220
(here the example is that of workpieces and measuring instruments
covered by the ISO standard 14253-1) by 85% [171]. Elster uses the
Bayesian approach to measurement uncertainty to deal with the case of
errors from analogue to digital conversion [172]. The problem of
evaluating uncertainty of a result consisting of only a single measure-
ment is treated in a Bayesian framework employing prior information
about the likely distribution of the quantity value [173].
Interval hypothesis testing, which can be interpreted in a Bayes
paradigm, is preferred by Hartmann et al. [174] to point hypothesis
testing for bias in an analytical experiment. Recently, Cowen and Ellison
[175] have reported how to use Bayes theorem to construct a confidence
interval for a measurement result near a natural limit (zero or 100%). For
measurements near zero, a uniform prior in a non-negative range forces
the posterior distribution to be positive. However if the likelihood is
assumed to follow a Normal distribution the range is insufficient for
small degrees of freedom, and a simple truncated range gives a better
interval. The IUPAC definition of detection limit is critically reviewed by
Spiegelman [176]. The use of Bayes theorem to set detection limits is
proposed and described. Michel showed how characteristic limits such
as the decision threshold, detection limits and confidence limits can be
calculated based on Bayesian statistics, taking into account all sources of
experimental uncertainties [177].
The least squares method and an empirical Bayes method for
calibration were compared by Unadkat et al. [178]. In the Bayesian
approach information from past calibration runs is also used. Bayesian
calibration in which the distributions of random components are
modeled, was expounded in 1989 by Hangos et al. [179]. An empirical
Bayesian method for processing linear calibration data using a single
calibration standard is described by Tod et al. [180]. An exact solution to
the Bayesian estimator was obtained which allowed calculation of the
Bayesian estimate of the calibration parameters without the use of
simulation.
A problem, not often a concern for field analytical chemists, is the
resolution of digital instruments. Frenkel and Kirkup [181] derive an
expression for the uncertainty imparted by a particular resolution. The
analogous problem of quantum shot noise has also been treated in a
Bayesian fashion by Bialkowski [182].
Quantity values of a NIST SRM were obtained by combining results
from different laboratories and techniques using a Bayesian statis-
tical model [183], after confirming commutability in an interlabora-
tory trial.
In an interlaboratory study of a medical diagnosis, qualitative
judgments made from plate tests of Brucellosis (Rose Bengal Plate
Test) were analyzed by Bayesian approach [94]. A beta distribution,
based on the result of each laboratory, was calculated and used to
estimate the probability of each laboratory giving a correct result and
its uncertainty.
More than a decade ago, probabilistic methods were strongly
recommended for assessing clinical enzyme methodology [184]. It was
recommended that at least the following statistics should be reported or
plotted: receiver operator characteristic (ROC) curves — the specificity
(false positive rate) against sensitivity (or true positive rate or fraction),
the rule-in and rule-out decision thresholds, and the clinical power of
the test (likelihood ratio). See also [185] for a tutorial on ROC. Testing for
drugs of abuse was the application for another perceptive discussion of
what is needed to ensure a reliable result [186]. Again, the sensitivity,
selectivity and false decision rates are requirements. The paper also
shows how combining more than one analytical technique can augment
the probability of a correct assignment. As expected, a field test kit
performs less well than a laboratory immunological method, which in
turn is beaten by laboratory chromatography. A more general discussion
is given by Fearn et al. [187], in which a risk analysis approach is given
that balances the cost of measurement (sampling and analysis) against
the cost of wrong decisions made. The Bayesian approach is seen in the
calculation of the cost of an inference which is calculated as the joint
probability distribution of a measured value given the true value, P(x|μ),
217
and the probability of the true value, P(x), weighted by the cost C(x,μ),
and integrated over all possible true and measured values
RR
CU = C ðx; μ ÞP ðx jμ ÞP ðμ Þdxdμ: ð14Þ
The paper gives different models for the different probability
densities and costs. For other examples of risk-based Bayesian
approaches see [27,37,188–190].
An interesting approach to the incorporation of expert opinion in
relation to linear regression models is given by Garthwaite and Dickey
[191].
Uncertainty of qualitative analysis, the assignment of identity to a
sample, was discussed in a Bayesian framework in a pioneering paper
by Ellison et al. [192]. Further papers have contributed to the debate
[193,194]. The earliest examples of Bayes theorem applied to
qualitative analysis were by Neubock et al. in 1992 [195] on ICP-MS
data, and Kulkarni et al. who analyzed DTA data [196].
9. Environmental chemistry and occupational health and safety
Matching of oil spills to putative sources using analytical data is a
problem exacerbated by environmental degradation. A Bayesian
analysis of correlations between spectra in an EPA database has
shown a high probability of match can be achieved by fitting
distributions of results of known systems [197]. Earlier Bayes theorem
had been used to select chromatographic features in a classification of
fresh and weathered crude oils [198]. Bayesian and maximum
likelihood methods for assigning environmental regulatory limits
have been shown to be superior to parametric bootstrapping [188]. To
determine an area around a well that captures water requires
inversion of the arrival times of released tracers and analysis of
conductivity data [199]. Monte Carlo sampling of possible conductiv-
ity realizations allowed assignment of probability based weights.
Parameters of the error model were removed by marginalization.
Combination of multiple tests of soil slippage was achieved by
application of Bayes theorem [200].
Determining air pollution sources from multivariate receptor data
benefits from a Bayesian approach using MCMC schemes, which can
give the number of components, parameterized spectra and con-
fidence intervals [201]. A patent describes how to construct a Bayesian
classifier from a library of responses of sensors from an electronic nose
[202], in order to decide where the particular odor comes from. Uses
have been in assigning sources of odor within an abattoir, and in
sewage works and other smelly industries.
Ecological modeling appears to lend itself to probabilistic methods,
being driven by complex variables for which distributions might be
the only information concerning their values, and a need to determine
the inverse forms of these models. An example study by Dowd and
Meyer [203] investigates a probabilistic approach for the inverse
problem associated with blending time-dependent ecosystem models
and observations. Prior information, ecological dynamics and sub-
stantive knowledge about uncertain parameters, are combined with
available measurements. Posterior estimates of both the time-varying
ecological state variables and the model parameters were obtained,
along with their uncertainty.
A Bayesian approach to retrospective exposure assessment is given
by Ramachandran [189,190]. Some assumptions of his approach were
robustly criticized by Burstyn and Kromhout, who questioned the
validity of weighting the opinion of ‘un-calibrated’ health profes-
sionals in assessing exposure. See [204] for the correspondence and
reply. Congdon considers modeling of sources of uncertainty in
measures of health status by using Bayesian sampling estimation
methods to produce a distribution of summary outcome measures
[205]. His paper reviews issues in assessing needs and outcomes at the
218 D.B. Hibbert, N. Armstrong / Chemometrics and Intelligent Laboratory Systems 97 (2009) 211–220

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NATO: North Atlantic Treaty Organization
NIR: near infrared
NIST: National Institute for Standards and Materials
NMR: nuclear magnetic resonance
Glossary PIXIE: proton induced X-ray emission
PLS: partial least squares
RNA: ribonucleic acid
ANN: artificial neural network ROC: receiver operator characteristic
BIC: Bayesian information criteria SBR: sequential Bayesian regression
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BSD: Bayesian spectral deconvolution SRM: standard reference material
DNA: deoxyribonucleic acid USEPA: United States Environmental Protection Agency
DTA: differential thermal analysis
EPA: Environmental Protection Agency
FTIR: Fourier transform infrared