Statistical Methods in Medical Research 2000; 9: 359–394

Data mining in brain imaging

Vasileios Megalooikonomou, James Ford, Li Shen, Fillia Makedon Department of
Computer Science, Dartmouth Experimental Visualization Laboratory, Dartmouth College,
Hanover, New Hampshire, USA and Andrew Saykin Brain Imaging Laboratory, Departments
of Psychiatry and Radiology, Dartmouth Medical School, Dartmouth Hitchcock Medical Center,
Lebanon, New Hampshire, USA

Data mining in brain imaging is proving to be an effective methodology for disease prognosis and
prevention. This, together with the rapid accumulation of massive heterogeneous data sets, motivates the
need for efficient methods that filter, clarify, assess, correlate and cluster brain-related information. Here,
we present data mining methods that have been or could be employed in the analysis of brain images.
These methods address two types of brain imaging data: structural and functional. We introduce
statistical methods that aid the discovery of interesting associations and patterns between brain images
and other clinical data. We consider several applications of these methods, such as the analysis of task-
activation, lesion-deficit, and structure morphological variability; the development of probabilistic atlases;
and tumour analysis. We include examples of applications to real brain data. Several data mining issues,
such as that of method validation or verification, are also discussed.

1 Introduction

Data mining in brain imaging is an emerging field of high importance for providing
prognosis, treatment, and a deeper understanding of how the brain functions. The
field of data mining addresses the question of how best to use this data to discover new
knowledge and improve the process of decision making. The discovery of associations
between human brain structures and functions (i.e. human brain mapping) has been
recognized as the main goal of the Human Brain Project,1 which is a high-priority
project funded by several government initiatives. Mining problems can be grouped in
three categories:2 identifying classifications, finding sequential patterns, and
discovering associations. Although data mining is a powerful knowledge discovery
technique, there are constraints in the way it can be applied: it is application-
dependent, different applications usually require different mining techniques, and
data must be of a certain size and format.3 In this paper we survey current mining
methods, give a critical review of the main computational obstacles that lie behind our
ability to perform automatic data mining on brain imaging and propose some
solutions.
There are various problems in mining of brain images that need to be addressed.
The first problem is that most fundamental mining algorithms (rule-based learning
systems, neural networks, decision trees, Bayesian networks, logistic regressions, and
so on), which have been used with great success in medicine, assume that data sets
contain only simple numeric and symbolic entries. It is important, therefore, to

Address for correspondence: V Megalooikonomou, Department of Computer and Information Sciences, Temple
University, 314 Wachman Hall, Philadelphia, PA 19122, USA. E-mail: vasilis@cis.temple.edu

Ó Arnold 2000 0962-2802(00)SM221RA

360 V Megalooikonomou et al.

consider how to preprocess brain images (multidimensional arrays of data) so that we

can transform them to data representations which are amenable to data mining
techniques. A second problem is that, although there are algorithms for classifying
images, there is a lack of effective algorithms for learning from images directly.4
Again, this implies the use of methods that transform images to a format conducive for
learning algorithms. Most early medical analysis ignored the image or raw sensor
portions of the medical record or summarized them in a very simplified form (e.g.
‘normal’ or ‘abnormal’). A third problem in mining brain images is the heterogeneity
of the brain imaging data: different modalities, formats and resolutions prevent a
common analysis and require integration. Integrating data from different studies often
means integrating different formats, which, in turn, implies imposing several
assumptions on the data representation. Many studies today, especially those using
functional imaging, only focus on a specific clinical question and deal only with a
small set of subjects, mainly due to the high cost of acquiring image data.
Other difficulties inherent in mining of associations in brain images are that: (1)
due to inter-subject variation and noise, a large number of subjects have to be studied;
(2) functions may correspond to more than one location and can relocate in the
presence of structure abnormalities; (3) brain lesions and other abnormalities have a
complex spatial distribution, typically covering multiple brain structures; and (4)
normal brain function can be affected in varying ways due to the complexity of the
functional organization of the human brain.
These obstacles aside, there have been recent technological advances that make
available enormous amounts of data. Imaging studies of the human brain at active
medical institutions today routinely accumulate more than 5 terabytes of clinical data
per year. Data in this domain usually consist of three-dimensional (3-D) images from
different medical imaging modalities that capture structural (e.g. MRI,y CT,z
histologyx ) and functional/physiological (e.g. PETjj , fMRI,{ SPECTyy ) information
about the human brain. On the other hand, there is now a wide availability of non-
invasive methods for assessing macroscopic brain structure, particularly magnetic
resonance (MR) techniques that complement clinical functional assessment.5 Also,
there is continued development of improved functional imaging techniques and
normalization methods. Greater computer capabilities are leading to the creation of
large databases of structure/function information, the efficiency of which, depends on
interoperable multimedia data representation that is easy to search. This trend is
reflected in the work of Fox et al.,6–9 Evans et al.,10,11 the QBISM database by Arya et
al.,12 the BRAID database by Letovsky et al.,13,14 the BrainMap database of neuro-
imaging data,15 and other neuroimaging databases.16,17
The problem of multidimensional data (e.g. brain images), can be solved with newer
mining methods which are applied directly to the images in order to capture most of
their information content. As was mentioned, mining is heavily dependent on
statistical methods for discovering associations and classifications among disparate
yMagnetic resonance imaging: shows soft-tissue structural information.
zComputed tomography: shows hard-tissue structural information.
xHistology images are acquired by physically slicing and photographing tissue.
jjPositron emission tomography: shows physiological activity.
{Functional-magnetic resonance imaging: shows physiological activity.
yySingle photon emission computed tomography: shows physiological activity.
 Data mining in brain imaging 361

types of data. We exploit this fact and consider methods that combine the information
from image and behavioural data about the brain and present methods for developing
probabilistic brain atlases. The results of these methods are new representations of the
information content of brain images and statistical maps.
The rest of this paper is organized as follows: in Section 2 we present the
preprocessing phase of data mining in brain imaging, including the segmentation and
spatial normalization of images. Although smoothing and reduction of noise can be
considered to be part of preprocessing, here we include them as part of the mining
methods in Section 3. In Section 3 we present mining methods that have been used in
structural and functional imaging. These methods are useful for: (a) the efficient
discovery of associations between structures and functions; (b) the classification of
structural information, including both normal structures and abnormalities such as
tumours; and (c) recently, the discovery of associations between gene expressions,
morphology, and function. In Section 4 we present important issues in mining of brain
images that are common to structural and functional brain data. We also consider the
problem of verification of mining methods. This review concludes with a discussion in
Section 5.

2 Data preprocessing

After image data is collected for each subject and before mining is performed, the data
has to pass through a preprocessing phase. This phase identifies and normalizes the
brain objects to be stored in a database and mined later. In anatomically related
studies, after an anatomical (i.e. structural) image is collected for each subject, each
lesion, area, or structure of interest is delineated (segmented) as a region of interest
(ROI) on each slice automatically, semi-automatically, or manually. Extensive work
has been done on automating image segmentation.18–21 The first segmentation
methods were solely intensity based.22 However, since many structures were not
distinguishable on the basis of signal intensity alone, prior spatial information was
incorporated either in the form of intensity gradients,23 prior spatial probability
distribution over signal intensity,18,23,24 or by registering the image to a segmented
atlas25–27 using a spatial probability map for each voxel.28
Using the slice data, each ROI is reconstructed in three dimensions. Then, in both
functional and anatomical images, normalization or image registration has to be
performed to make image data comparable across subjects without morphological and
acquisition variability. This process maps homologous anatomical regions to the same
location in a stereotaxic space, such as the Talairach anatomical atlas.29 Several linear
and nonlinear spatial transformations have been developed to bring the 3-D atlas and
the subject’s 3-D image into register, i.e. spatial coincidence.27,30–32 As an example, the
effect of registration of an MR image to the Talairach atlas using a nonlinear method
based on a 3-D elastically deformable model32 is presented in Figure 1.
In addition to 3-D image data, modern brain image databases usually contain a set
of generic anatomic atlases of the human brain that model the exact shapes and
positions of anatomical structures. A raw MR or fMR image does not identify the
structure to which each voxel (3-D volume element) belongs, but an anatomical atlas
362 V Megalooikonomou et al.

(a) (b) (c)

Figure 1 A slice of (a) original MR image, (b) atlas, and (c) atlas image overlaid on the deformed MR image.
Picture from Megalooikonomou et al.97

can supply this information (with the accuracy of the registration methods) when
overlaid on the image (see Figure 1). A variety of brain structure maps have been
derived, at several spatial scales, from 3-D tomographic images,33 anatomic speci-
mens,29,34,35 and a variety of histologic preparations that reveal regional cyto-
architecture36 and molecular content. Other brain maps have concentrated on
function,37,38 or neuronal connectivity and circuitry.39,40 Here, for clarity of
presentation, we concentrate on the widely used Talairach atlas.

3 Data mining

We first present methods for discovering associations between brain functions and
structures. Traditionally, two approaches have been employed for functional brain
mapping. The first approach seeks associations between lesioned structures and con-
comitant neurological or neuropsychological deficits – for example, between trauma
lesions and deficits like left visual field deficit. The second approach measures brain
activation in subjects as they are asked to perform certain tasks. We present methods
for both approaches. The problem of efficiently finding similar ROIs in brain image
databases is also addressed. We present methods for extracting knowledge about the
morphological variability of brain structures and about abnormalities such as
tumours. Methods that can be potentially applied to both structural and functional
imaging are also presented.

3.1 Functional imaging of the brain

Functional brain imaging uses technologies such as PET, SPECT or fMRI with
specifically designed experiments to identify activated regions of the brain under
different conditions. The cumulative nature of PET greatly limits its spatial and
temporal resolution. fMRI has much better temporal resolution, and a spatial
resolution on the order of 2–4 mm that is limited by the characteristics of the
underlying vascular structure (Ogawa et al.41 present an in depth review of fMRI).
Recently, diffusion tensor imaging (DTI) has emerged as a new application of MR
technology to the problem of human brain mapping. DTI calculates 3-D diffusion
 Data mining in brain imaging 363

tensor maps by measuring water proton mobility in diffusion weighted MR images.42

DTI can be used to indirectly image nerve fibre bundles, especially those in white
matter areas that are connecting links between various (grey matter) brain areas and
‘invisible’ so far in other imaging.
The data from functional imaging scans are typically in the form of measurements at
thousands of voxels. In PET, a voxel measurement reflects the amount of activity in a
brain region. In fMRI, a voxel’s time series of measurements is meaningless by itself,
but becomes useful when compared to another series of measurements at the same
place under different conditions. This is possible after registration and motion cor-
rection.43–46 Since different subjects may have different strategies for accomplishing
the same task, it can be useful to be able to average all subjects in a multi-subject study
to see the common areas of activation.45 Averaging multiple subjects also increases the
statistical power of the analysis, and is usually necessary for fMRI with its low signal-
to-noise ratio. Smoothing is usually then performed by applying a spatial smoothing
filter to reduce the effect of motion that was not completely removed, and other un-
wanted noise.47 The typical choice is a low-pass Gaussian filter in the spatial domain,
which smooths high frequency variation in the data. Several researchers have suggested
that the use of Gaussian filters for denoising in the spatial domain introduces unwanted
biases,48–53 and that the optimal filter width is a function of the size of activation
foci,50,54 which cannot generally be determined a priori except possibly by reference to
underlying neuroanatomy. The low-pass filter approach will also blur and displace
activated areas and remove the areas of least activation, reducing spatial resolution.
There have been suggestions for addressing these limitations of Gaussian filtering
by focusing on signal restoration instead of noise removal, looking at multiple scales to
overcome the problem of scale-specificity, or using approaches that do not impose a
priori models on the data. The scale-space approach50,55,56 builds a multi-resolution
representation of functional data. Voxels are organized in clusters (called ‘blobs’50,55)
that may be of different shapes and sizes at different scales. Blobs themselves are
hierarchically organized, with ‘blob trees’ dividing scales higher in the tree (lower
resolutions) into smaller blobs at lower scales, down to individual voxels at scale 0.
Each scale s > 0 corresponds to the convolution of the original n-D signal with a
Gaussian kernel of width s.50 The multifiltering approach57 is similar in that analysis
is done on smoothed and unsmoothed data (although only one level of smoothing is
used) for the purpose of picking up large regions of relatively weak activations. Other
analysis techniques operate directly on the data, for example in the wavelet
domain,58–60 and do not explicitly smooth the data. In this case, the fact that back-
ground noise is distributed compared to spatially localized signals can aid in useful
extraction of the signals. The complex-denoising noise reduction process can also
increase signal-to-noise by thresholding discrete wavelet transform coefficients.61
Temporal smoothing is also often done in fMRI, and the signal series at each voxel is
usually convolved with some approximation of the haemodynamic response function
(HRF) – e.g. a Poisson function, the Gamma function, a linear combination of the
Gamma function and its temporal derivatives, or the Gaussian function – that is
chosen heuristically.62 This approach identifies activated voxels, although particular
analysis methods can take many forms. There has been recent interest in improving
HRFs.62,63
364 V Megalooikonomou et al.
3.1.1 Statistical parametric mapping (SPM)
One of the most common analysis approaches currently in use, called statistical
parametric mapping (SPM),64,65 analyses each voxel’s changes independently of the
others and builds a map of statistic values for each voxel (see Figure 2). The
significance of each voxel can be ascertained statistically with a Student’s t-test, an F-
test, a correlation coefficient, or any other univariate statistical parametric test43 (more
details about the use of t-test in SPM are in appendix A1). The result of the t-test is a t-
value that, when indexed with the number of degrees of freedom, gives a probability
value indicating how likely it is that this difference could occur by chance. The
significance threshold (alpha value) is typically chosen to be 0.05 or less, indicating a
5% or smaller chance of a ‘false positive’ decision of significance. The t-value can also
be expressed as a Z-score, indicating how many standard deviations the t-value
represents on a Gaussian distribution. Z-scores and alpha values are the most popular
means for reporting the significance of this difference. The t-test is mathematically
equivalent to a one-way analysis of variance (ANOVA), and both can be expressed in
the general linear model for regression analysis64
Y ðtÞ ¼ X ðtÞ þ "ðtÞ
at each voxel. The general linear model finds (and tests significance of) linear
regressions between two data sets X and Y for each member of X (including dummy
members added to represent experimental conditions). Methods based on general
linear models have more variables (voxels) than samples (e.g. the number of
examinations) and thus are severely underconstrained.
By applying a uniform threshold of statistical significance it is possible to determine
which voxels are likely to have had significant changes between conditions, and with
what likelihood, assuming a null hypothesis of no changes between conditions. Data
from individuals can be combined into groups, in which case statistical inferences can
be drawn either about the significance of differences between subjects, or the
likelihood of consistent activation in the population from which the subjects were
drawn.66 Some early studies have examined the possibility of doing post-analysis on
statistical maps, allowing comparisons of activations between independently analysed

Figure 2 Statistical parametric map. These displays of a statistical parametric map (SPM), produced using the
SPM99 software package, show two views (one overlaid on a surface map, the other an axial slice) of 3D brain
activations for a simple motor task (courtesy Brain Imaging Lab, Dartmouth-Hitchcock Medical Center).
 Data mining in brain imaging 365

subjects.55,67 One problem here is that when using voxel data, comparison of different
scans may not align activations that are slightly misregistered. Recently, the spatial
extent, i.e. the area of activation, has been used to detect significant regions of
activation. If a spatial extent of activation is reported, however, it is sometimes only
given as a voxel count above a threshold, which has been found to be a very unstable
indicator of activation across trials.68
Another issue of concern in functional imaging is the consistency of observations
across subjects. It is common for some activations during a study to be similar across
subjects (and thus significantly correlated with the task under study), and for others to
be idiosyncratic. There has been some report in the literature about the difficulty of
reproducing voxel level significance maps in fMRI.68,69 In the case of Tegeler,69 even
the 2% most significant voxels were found to vary considerably across runs, subjects,
and analysis techniques. Variability in activation maps is a concern; however,
reproducibility of fMRI activations at a regional level has been found to be good in
general across sites, subjects, and techniques,70 and comparisons of signal changes
rather than significance values may address problems in voxel-level comparisons.68
A third issue in functional imaging is the choice of analysis methods for generating
activation data. Several reports have substantiated the difference in activations
observed using different analysis techniques.69,71,72 These may be a concern in a large
database system. However, if results are tagged according to the analysis technique
and parameters used to generate them, multiple analysis methods may actually be
beneficial in supporting a ‘pluralistic’ strategy for analysis.72
A fourth issue in functional imaging is the necessity of limiting assumptions in
analysis. For example, the SPM model assumes a uniform distribution of noise with
covariance between voxels estimated by a Gaussian distribution that decays with
increasing distance, and unfortunately not all data conforms well to this noise model
(noise from unmodelled biological variability such as venous activity may not, for
example). It is difficult to assess the extent that conditions deviate from the model in
practice,52 but tests with synthetic data have demonstrated large biases in the false
positive rate73 as a result of low frequency physiological fluctuations and a variation of
signal-to-noise ratio with imaging rate. Techniques for correcting long-term changes
in mean signal intensity can improve the sensitivity of statistical analysis in this
particular case.74

3.1.2 Other methods

An analysis method similar in concept to statistical parametric mapping is
correlation of observed signal changes with experimental blocks.75–79 This method
can be applied at the voxel level, with a resulting activation map much like an SPM
(but not necessarily statistical in nature). Other variations analyse groups of voxels
with an overall mean change in signal,80 incorporate prior information81 or wavelet
analysis82 into an SPM-type framework, use expectation maximization to estimate
labelling parameters in a Markov random field model,83 or combine tests for
significance with detection of high intensity signals.84
Another approach used in the analysis of brain activations is to analyse relations
between voxels, by using, for example, a six-dimensional correlation map correlating
every voxel with each other voxel in order to detect correlated changes85 or by using
366 V Megalooikonomou et al.

structural equation modelling to relate functional neuroimaging signals to underlying

neurobiological activities.86 Similarly, one can use an empirical assessment of the
relation between data in random pairs of conditions in place of statistical tests of
significance87 although this is computationally intensive. Other approaches are based
on the generation of cross-correlation image maps,88 Fourier-analysis-based time-
series regression models,89 principal component analysis,90 partial least squares,76
independent component analysis,91 or structural equations to model functional
connectivity among ROIs.92 Spatial-lattice models are often applied to image analysis;
these techniques are often based on Markov random fields, with inference techniques
based on various modifications of likelihood-maximization procedures.93
Another alternative is to divide brain images into meshes, treat functions as classes
and meshes as attributes, and find rules like ‘A and B ) positive’, which means if
mesh A and mesh B are active, then some function is positive/on:94 thus the problem
can be reduced to supervised inductive learning. The usual inductive learning
algorithms such as C4.595 do not work for this problem, however, because (1) there are
strong correlations between attributes and (2) there are usually too many attributes
(say 100  100 = 10 000) and too few samples (say 100). However, nonparametric
regression can be applied to solve these problems. One algorithm for the discovery of
rules from brain images consists of the following two steps: (1) a nonparametric
regression96 is applied on the training data set. The results are linear formulas of the
form y ¼ p1 x1 þ . . . þ pn xn þ pnþ1 , where y is a dependent variable (i.e. function), and
x1 ; . . . ; xn are Boolean independent variables (i.e. grids). (2) Rules are extracted from
the linear formula y (y is normalized to [0,1]) by converting it to a Boolean function y0
using an approximation: if y  0:5, then y0 ¼ 1; otherwise, y0 ¼ 0. Since the naive
approach always runs exponentially to complete the second step and becomes un-
realistic in practice, a better algorithm is to generate terms from low order to high
order while applying a pruning strategy. Experiments on artificial data showed:94
(1) when there are no correlations between adjacent attributes, the accuracies are
almost the same as the accuracies of C4.5, and (2) when there are strong correlations
between adjacent attributes, the algorithm works better than C4.5 in terms of the
accuracy of the result.

3.2 Structural imaging of the brain

3.2.1 Lesion-deficit analysis

In principle, lesion-deficit data could be analysed using methods similar to those for
activation studies (e.g. SPM). We now present several additional statistical methods to
determine structure–function relations through the study of lesions and associated
deficits. After the preprocessing, i.e. the segmentation of lesions and registration of the
binary images to a common standard, the binary images consist of ‘normal’ and
‘abnormal’ (lesioned) voxels. This type of structural image data, combined with the
behavioural variables, form the data for each subject. Mining methods for the
discovery of the structure–function associations from this data can operate on a
resolution range from the spatially distinct structures of an anatomical atlas (atlas-
based analysis) to the voxel level (voxel-based analysis).97
 Data mining in brain imaging 367

3.2.1.1 Atlas-based analysis. In the case where anatomical structures represent

functional units, the atlas-based analysis is more sensitive than voxel-based analysis
since the atlas provides significant prior knowledge. The first step in the atlas-based
analysis is to calculate for each structure si and subject pj , the fraction of lesioned
volume, fsi ;pj , which is defined as the volume of the lesioned part of si divided by the
volume of si . These fractions form the continuous structural variables. Here, we
present methods for both categorical and continuous structural variables.13,14,97 In the
case of categorical variables, the lesioned fraction determines if a structure is lesioned
(abnormal) or not. For example, a patient might be treated as having a lesion in a
structure if the intersection of all his/her lesions with the structure is at least one
voxel. To eliminate thresholding effects, the atlas structures can also be analysed as
continuous variables, considering for each one the fraction that is lesioned.
When the search for the model that explains the data can be directed through
specific hypotheses or prior knowledge, the situation is easier. Hypotheses can be
formed after using explorative visualization or other methods, and can be tested using
statistical analysis. An example where visualization helps to reduce the search space
for a model is shown in Figure 3. If there is little preconception about the
relationships between the variables, all the possibilities may have to be explored. This
exploratory, or data mining, analysis is presented below. There are two analysis
approaches one can follow: bivariate (pairwise) and multivariate.

Bivariate analysis. Let F be the number of functional and S be the number of

structural variables respectively. In the case of categorical structural variables, F  S

ADHD+

ADHD-

Tal-113 Tal-116 Tal-119 Tal-124

Figure 3 Visualization helps reducing the search space for the model that explains the data. Sum of lesions for
the ADHD+ and the ADHDÿ group of patients (four slices of the Talairach atlas are shown for each group). The
right putamen and left thalamus are highlighted. Picture from Megalooikonomou et al.181
368 V Megalooikonomou et al.

two-way contingency tables are constructed and for each the Fisher exact test98 is
computed. The associations between structures and deficits are sorted in order of the
p-values returned from the exact tests, and the ones with the lowest p-values are
reported. For the same type of analysis with continuous structural variables one can
use the Mann–Whitney test and logistic regression analysis (the Mann–Whitney stati-
stic is appropriate because the distributions of the fractions of lesioned volumes are
not Gaussian). In exploratory analysis of either categorical or continuous structural
variables, computing a statistic for many pairwise tests leads to the multiple com-
parison problem, i.e. the situation where a certain undesirably high number of the
tests are expected to be positive by chance (see Section 4.1 for a more complete
treatment of the multiple comparison problem).

Multivariate analysis. Multivariate analysis may find complex multivariate associa-

tions not found by multiple uses of bivariate statistics. For example, consider a deficit
that is associated with two structures and appears only when both of them are lesioned.
Multivariate analysis is free of the multiple comparison problem, since it evaluates an
entire model with one statistic. One multivariate extension of the chi-square test for
categorical variables is log-linear analysis; logistic regression is another multivariate
method that can be used to relate the log-odds of having a particular deficit to the
fraction of lesioned structures. The stepwise logistic regression has also been used,97
where the algorithm for discovering the model that explains the interactions starts
with no associations and a greedy approach is applied to add (or delete) associations
based on their relative strength.

3.2.1.2 Voxel-based analysis. Atlas-based analysis results are only as good as the atlas
that is being used. Instead of imposing any high level structure on the image data, one
can analyse them on a voxel-by-voxel basis. Voxels are typically labelled as either
normal or abnormal, and thus structural variables are in this case categorical. Given
that the number of voxels that are considered is typically on the order of 107 , a like
number (i.e. 107 ) of Fisher exact tests have to be performed for each of the functional
variables that are examined. This procedure can be seen as clustering the voxels by
functional association.97 The calculation of the contingency table and the Fisher exact
test is computationally intensive, and the multiple-comparison problem is also severe
due to the large number of tests that must be performed. However, in this case it can
be attacked with clustering analysis since false positives will not tend to cluster.
Voxel-based regression analysis can also be used to determine whether voxels in a
certain region are associated with a functional variable. One can construct a regression
equation that relates lesions in a sphere of a given radius and centre to a deficit, and
the ‘causal brain region’ in which lesions are most strongly associated with that deficit
can then be identified.13,97 Let l be a lesion, o a sphere, vðrÞ the volume of a region r,
and iðr1 , r2 Þ the intersection of two regions r1 and r2 . Then the identification of the
causal region is done by calculating the optimal centre and radius for the logistic
regression equation:
log itðdÞ ¼ log ðoddsd Þ ¼ afs þ b
 Data mining in brain imaging 369

where oddsd ¼ pd ð
Þ=ð1 ÿ pd ð
ÞÞ, pd ð
Þ is the probability of having a certain deficit d,
fs ¼ vðiðl; oÞÞ=vðoÞ is the fraction of the sphere that is lesioned, a=(log odds of d)/
(lesioned fraction of sphere volume), and b is the prior log odds of deficit d.
Given the centre ðx; y; zÞ and the radius r of the sphere, one can find values for the
parameters a and b such that the sum of squares of residuals is minimized. The goal is
to optimize the sphere parameters ðx; y; z; rÞ to obtain the best fit of the data to a
regression line. The solution is the sphere that best discriminates between lesions that
are and are not associated with deficit d. This nonlinear optimization procedure is
computationally intensive, and cannot describe multifocal functional associations.

3.2.1.3 Results from mining lesion-deficit associations. In this section we present results
from the mining process in BRAID.13,14 The Brain Image Database includes images
and clinical information from over 700 subjects from two different studies: the
Cardiovascular Health Study (CHS)99 and the Frontal Lobe Injury in Children
(FLIC) study.100 Visualization applied prior to the analysis procedure can help direct
the analysis by choosing certain structures of the anatomical atlas to examine further
using the statistical tests. Figure 3 shows the sum of lesions over all subjects that did
and did not develop ADHD (Attention-Deficit Hyperactivity Disorder), i.e. ADHD+
and ADHDÿ, respectively. Based on these images and on previous research
implicating a frontal lobe-basal ganglia-thalamic pathway, the right putamen and
the left thalamus (highlighted in Figure 3)y were chosen for further analysis using the
Fisher exact test for categorical and the Mann–Whitney test for continuous structural
variables. The p-values in Table 1 confirm a strong association between lesions in the
two structures and development of ADHD.
Running an exploratory analysis on the CHS data set (300 subjects) using the chi-
square test to evaluate two-way contingency tables for all pairwise combinations of
atlas structures (90) and functional variables (14) returns a list (sorted by p-value) of
structure–function associations.13,97 The five most significant associations are
presented in Table 2. Highly significant lesion-deficit associations detected by BRAID,
such as visual field deficit and lesions in contralateral orbital or cuneate gyrus, are also
consistent with current clinical knowledge.101 The incorrect association between the
left hippocampus and a right visual field deficit is due to registration error, since the
hippocampus is next to the optic radiations that are very well known to be correlated
with a visual field deficit.
Preliminary stepwise logistic regression analysis using continuous structural
variables from the FLIC data set show similar results for the development of ADHD.
This method identifies the left SupCerebellarA (which is lateral to the left putamen
area) as a strong predictor. Results from a preliminary voxel-based analysis for the
ADHD variable of the FLIC data set are presented in Figure 4(a). Each voxel
represents the p-value for the association between the voxel being lesioned and the
development of ADHD. A 3-D reconstruction is shown in Figure 4(b). These results

yDue to the compromised connections between the frontal lobe and these two structures, it is believed that the frontal
lobe is not able to exert its normal oversight function to suppress impulsive urges and behaviours. A common
behavioural pattern in patients with ADHD is impulsivity and lack of self-control.
370 V Megalooikonomou et al.

p-value

(a)

(b)
Figure 4 Voxel-based analysis for development of ADHD. Six slices (a) of the Talairach atlas and a colour bar
that shows the correspondence between p-values and colour values are shown. (b) Visualization of the voxel-
based analysis p-value volume for development of ADHD. The higher the intensity the lower the p-value. Picture
from Megalooikonomou et al.97

are consistent with those of the atlas-based analysis. Figure 5 shows one representative
slice (119) of the Talairach atlas for the voxel-based regression analysis for ADHD.
These results are consistent with all the previous ones for ADHD.
 Data mining in brain imaging 371
Table 1 Visualization directed mining. Statistical analysis of selected Talairach atlas structures for association
with ADHD (FLIC data set)97

Structure Fisher’s exact p-value Mann–Whitney p-value

R putamen 0.065 0.033

L thalamus 0.095 0.093

Table 2 Explorative analysis The five most significant structure-function associations given by the chi-square
analysis on the CHS data set97

Structure Function Chi-square p-value S-Bonf. Correct. p-value

R globus pallid. R hemiparesis 0.00001 0.0039

L hippocampus R visual defect 0.00001 0.0095
R gyri angular L pronat. drift 0.00002 0.0195
R gyri orbital L visual defect 0.00003 0.0225
R gyri cuneus L visual defect 0.00003 0.0224

3.2.2 Structure morphology analysis

Several methods have been applied in extracting knowledge about the morphology
variability of brain structures. Study of the location, size, surface area, volume, and
shape of specific brain regions is critical for discovering normal brain organization, for
defining anatomically-driven search areas for brain activity in functional imaging
(PET, fMRI) scans, and for investigating pathological changes in the case of diseases
affecting these structures. Some of the same voxel-based analysis techniques described
in relation to functional studies have been applied to anatomy as well; in general,
voxel-based morphometry identifies changes in gray matter on a voxel-by-voxel
basis.102–105,186 This method is used to study the different composition of brain tissue
after macroscopic shape differences are discounted using spatial normalization.
Another common approach is to use a warping (deformation) of an individual’s
brain to an anatomical template (e.g. the Talairach atlas29) and gathers details about
the warping that are used in the analysis.106,107 A deformation function dðu; vÞ, defined
at each point ðu; vÞ of the atlas structure, S; of interest, measures the enlargement or
shrinkage associated with the transformation from an infinitesimal region around a
point in the atlas space to its corresponding infinitesimal region in the subject space.
In this method a comparison of two different brains or, more generally, two popu-
lations is achieved by comparing the corresponding deformation fields: regions with
statistically significant differences are regions of morphological differences between
the two populations. Results from applying this methodology106 to a study of the
corpus callosum for a small group of elderly subjects are shown in Figure 6. More
details on the use of a deformation function in the analysis of morphological varia-
bility can be found in Appendix A2.
Surface-based mesh modelling is a similar approach.108,109 After minimal regis-
tration a parametric mesh is stretched over the surface contour of a structure or ROI
372 V Megalooikonomou et al.

(a) (b) (c)

Figure 5 The optimal regression sphere (c) that best discriminates the two groups, i.e. between lesions that
are (a) and are not (b) associated with the development of ADHD. Picture from Megalooikonomou et al.97

(see Figure 7). It is then compared to an average parametric mesh that is formed by
calculating the mean and variation between corresponding points on the mesh.
Finally, displacement vectors are generated for each individual structure. A local
profile of change in structures in certain conditions can be provided through colour-
coded topographic maps (see Figure 8). This method first aligns each brain volume
using distance scaling to control for head size differences, allowing for inter-individual
and group comparisons. A strategy for creating a population-based brain atlas using

(a)

(b) (c)

Figure 6 Morphological variability of the corpus callosum between women and men for a group of elderly
subjects. The posterior part (in white) was found to be significantly larger in women than in men (a). The
average shape of the corpus callosum for (b) men and (c) women in a study by Davatzikos et al.106 Pictures
from Davatzikos et al.106
 Data mining in brain imaging 373

Figure 7 Extracting meshes (a) to create a cortical surface database, to search for differences where the
deformation is regarded as an observation from a random vector field. Variability is calculated based on 3D
displacement maps, which locally encode the amount of deformation required (b) to drive each subject’s gyral
pattern into exact correspondence with the average cortex for the group. Pictures from Thompson et al.184

volumetric warps is shown in Figure 9. The application of these methods in several

studies has already revealed differences in the shape and size of certain structures
related to gender (e.g. corpus callosum106,110), in disorders such as schizophre-
nia,107,111,112 in normal aging, and in Alzheimer’s disease.113 Probabilistic atlas
approaches have been used for studying both normal and abnormal brains.114
Another approach attempts to identify and register landmark configurations (defined
as point sets that correspond biologically across images).115 Image deformation
algorithms designed to accomplish these goals are useful for identifying and measur-
ing variations in structure, although they are not designed for tasks like finding
tumours or activations. The Procrustes distance is one of the core tools of image
deformation algorithms, and is calculated for two landmark configurations with the
same landmarks by minimizing the sum of distances between corresponding landmark
points while rotating around the normalized centroid of each. Finally, point-wise t-
tests, ANOVAs, and partial correlations116 as well as eigenvector and related
analysis115,117–119 have been used in computational neuroanatomy to study group
differences in morphology and its associations with cognitive variables.
Other related work is the study of human anatomy,120,121 which presents the most
difficult challenges to the understanding of typicality and variablity. While biological
shapes are highly structured, they are not rigid. Miller’s group have been using
Grenander’s deformable anatomical templates for the representation of typicality and
variability. For this, complex anatomical templates (human and macaque brains) are
annotated with coordinate systems defined within them. High-dimensional vector
fields applied to these coordinate systems carry the templates with all of its geometry
into the target. This allows for understanding modulo individual variation.

3.2.2.1 Morphological analysis of tree-like structures. Another tool for the analysis of
brain structure and function is through the morphological characterization of
neurological brain structures. Tree-like structures, such as nerve-fibre tracing in
374 V Megalooikonomou et al.

(a) (b)

Figure 8 Three-dimensional visualizations of structural variability, asymmetry and group-specific differences.

(a) Anatomical variability of the cerebral cortex in male schizophrenia patients and controls. Variability is shown
on an average surface representation of the cortex derived from schizophrenia (left) and normal control (right)
populations. Individual variations in brain structure in frontal association areas are greater in schizophrenia.
Variability is calculated based on 3D displacement maps, which locally encode the amount of deformation
required to drive each subject’s gyral pattern into exact correspondence with the average cortex for the group.
Picture from Narr et al.182 (b) Ventricle variability maps for Alzheimer’s disease. Pictures from Thompson
et al.183

Figure 9 Creating a population-based brain atlas to quantify local structural variations. A family of high-
dimensional volumetric warps relating a new 3D MRI scan to each normal scan in a brain image database is
calculated (I–II, above). The resulting warps encode the distribution in stereotaxic space of anatomic points that
correspond across a normal population (III), and their dispersion is used to determine the likelihood (IV) of local
regions of the new subject’s anatomy being in their actual configuration. Colour-coded topographic maps
highlight regional patterns of deformity in the anatomy of the new subject. Abnormal structural patterns are
quantified locally, and mapped in three dimensions. Pictures from Thompson et al.185
 Data mining in brain imaging 375

DTI MR angiography or confocal microscopy, are registered (after segmentation and

skeletonization) with standard structural and functional volumes. In addition,
morphological analysis of these structures using various path analyses tools is per-
formed. Morphological descriptors such as Sholl analysis,122 moment analysis,123–125
and fractal dimension analysis are used to support content-based retrieval operations
in 3D cell-centred neuronal databases.126,127 Recently, visual data mining techniques
combined with computational neural modelling have developed a very effective means
to detect morphological influences on neuronal function.128

3.2.2.2 Brain tumour analysis and classification. Classification is an important problem

in data mining. Classifiers are useful for building taxonomies of images and sub-
sequently performing image context based searches.129 Methods for finding similar
tumour shapes in structural images130 can also be used for brain tumours. Korn et al.
use concepts from mathematical morphology, namely the ‘pattern spectrum’ of a
shape, to map each shape to a point in n-dimensional space. Starting from a natural
similarity function (the ‘maximum morphological distance’), they first prove a lower
bound for it and then demonstrate how to search efficiently for nearest neighbours in
large collections of tumour-like shapes using R-trees131 and the ‘Feature index’ (F-
index) approach.132 The technique was applied to realistic tumour shapes generated
using an established tumour-growth model133 and the results were very encouraging
(see Figure 10). Fractal features and texture analysis have also been used for the
quantitative description and recognition of brain tumours in 3-D MR images.129

3.3 Combined structural and functional imaging of the brain

Structural and functional imaging are often combined. It is common to restrict
activation studies to a certain area of interest that corresponds to an anatomical
structure. Here, we present a new area of research where both structural and
functional images have to be mined together, and methods that can be potentially
applied to both.

3.3.1 Gene expression, morphology and function

Discovering patterns of gene expression and their complex interaction with brain
morphology and function is a fundamental goal in recent molecular biology and
neurobiology studies. In situ hybridization and MRI have provided very high
resolution images of gene expressions in animal models. In addition, gene expression
brain atlases for the mouse and the rat have started to appear.134–136 After the
registration of anatomic and gene expression images across modalities and subjects
through more involved methods137–141 than those presented in Section 2, spatial
statistics methods have to be applied to find associations between anatomic, genetic,
and nonimage variables such as behavioural measures, response to drugs, or onset of
disease. The main challenge in finding associations among patterns of gene
expressions and phenotype is the synthesis of temporal information, spatial
information, and static data. Similar work has been done in the analysis of functional
images (as described earlier) where changes in signal intensity occur in response to
376 V Megalooikonomou et al.

Figure 10 Query tumour images (left column) and their nearest neighbours, with respect to morphological
distance. Picture from Korn et al.130

processing different kinds of stimuli. However, considering that multiple genes can be
expressed in the same brain location, and that the time sequence of gene expression
may also be important, makes the problem even more challenging.

3.3.2 Bayesian networks

Multivariate analysis methods like log-linear regression and logistic regression
provide relatively simple methods for generating candidate models, usually relying on
modifications of greedy search and making assumptions about cell frequencies or total
number of samples that may not hold for rare cases. A more promising approach
generates models called Bayesian networks142 that consist of graphical structures
along with statistical independence models. This method scores each model M, and
returns the most probable model that could have generated the data D at hand (i.e. the
multivariate multinomial distribution that generated D).143,144
Briefly, a Bayesian network is a directed acyclic graph in which nodes represent
variables of interest, such as structures or functions, and edges represent associations
among these variables. Each node has a conditional-probability table that quantifies
the strength of the associations between that node and its parents. Given the prior
probabilities for the root nodes and conditional probabilities for other nodes, we can
derive all joint probabilities145 over these variables. An approach for generating a
Bayesian network from data is described in Appendix A3.
Recently the Minimum Description Length (MDL) principle has been applied to
Bayesian network learning.146,147 The principle states that the best model of a
collection of data is the one that minimizes the sum of the encoding lengths of the data
and the model itself.148 The MDL metric is defined to measure the total description
length DL of a network structure G, which is the sum of description lengths of each
node.147,149 The description length of each node is defined from two components, the
network description length and the data description length. The first is the description
length for encoding the network structure, which measures the simplicity of the
network. The second is the description length for encoding the data, which measures
the accuracy of the network.
 Data mining in brain imaging 377
3.3.3 Behavioural imaging
Another approach for modelling structure–function relationships is to transform
neuropsychological test scores that assess cognitive functions to a 3-D spatial
representation of the predicted sites of regional dysfunction. Gur et al.150 presented
such an algorithm for display and analysis of neuropsychological test scores that
produces regional values from standardized (z-transformed) neuropsychological test
scores using the formula:
X  X 
Bj ¼ W ði; jÞSi = W ði; jÞ

where Bj is the index of behavioural functioning for a given region, W ði; jÞ is the
weight assigned to the jth brain region for the ith behavioural score, and Si is the test
score. The method was demonstrated on a sample of hemi-Parkinson patients151 and
later used to examine the sensitivity of cognitive test scores to lesions in specific ROIs,
inter-expert agreement, and intra-expert reliability.152 The method can be used to
relate cognitive test scores to the results of structural and functional imaging, and has
great potential for integrative data mining. Turkheimer et al.187 also quantitatively
examined the relationship between neuropsychological test scores and lesion locations
on structural neuroimaging.

4 Important issues in mining of brain images

4.1 The multiple comparisons problem
Using an exploratory analysis and computing a statistic for many tests (as in the case
of pairwise test) leads to the multiple comparisons problem, i.e. the situation where a
certain undesirably high number of the tests are expected to be positive by chance. A
standard Bonferroni correction98,153 suggests that one divide the significance threshold
by the number of independent tests performed. This typically overestimates the
number of independent tests performed, since test results are often correlated for
neighbouring structures (activations or lesions often extend over neighbouring
structures), and leads to loss of sensitivity. A heuristic modification of the Bonferroni
correction, the sequential Bonferroni correction,98 can be used to get less pessimistic
results. To do this, one sequentially increases the value of the significance threshold as
hypotheses are evaluated. In task-activation studies, increasing the threshold for
statistical significance increases the number of false positive activations that are
detected.
The Bonferroni correction only applies in the case where a null hypothesis is to be
rejected (i.e. any lesions or activations at all are treated as unexpected). The correction
is not necessary in the case where a hypothesized region of lesion/activation or a
structure is chosen,154 since in this case the null hypothesis of no changes is
necessarily relaxed. If the cross-correlation between adjoining voxels is considered, a
higher threshold can be used more safely. Single voxels that have signal changes of low
significance may be the result of noise, but several voxels together that have a
correlated change have a higher likelihood of representing a true lesion or
activation.155 One heuristic alternative to the Bonferroni correction is cluster filtering;
in this method, clusters smaller than a certain size (number of voxels) are simply
378 V Megalooikonomou et al.

discounted. Taking advantage of this kind of approach increases sensitivity, but it also
adds risk of error at the cluster level (rather than only at the voxel level).84 The overall
error rate can still be controlled, so the net effect is to reduce errors.

4.2 Clustering voxels

Clustering is the process of finding, in a contiguous spatial region, voxels with
similar significance in a voxel-based activation or lesion-deficit study. Clustering can
be done after independent significance tests are performed by grouping adjacent
significant voxels, or clusters can be calculated directly from the data by detecting
correlated changes.85,156–158 In the latter case, clustering can be viewed as a method for
generating hypotheses that statistical testing can evaluate.159
Clustering has been used to differentiate functional activations from other activity
in the brain using statistical methods160–165 and neural networks.166,167 Clustering has
been claimed as a higher quality analysis tool than correlation analysis because of its
ability to detect unanticipated difference in response, such as differing levels of
activation168 or similarities in the time-course of fMRI signal changes and stimuli.163
The cluster filtering approach mentioned earlier depends on having an estimate of the
likelihood of each cluster size, which depends on the noise distribution. Images of the
noise distribution can be obtained by, for example, subtracting the results of one
condition from a repetition of that condition. Using simulated images derived with the
same spatial correlation as these images, one can estimate the probability of observing
clusters above a given size and thus the probability of each cluster in the original data.164
Then, clusters below a desired probability threshold can be discarded as too uncertain.

4.3 Verification of mining and power considerations

In previous sections we discussed methods for finding associations between tasks
and activations, or between lesions and deficits. However, the evaluation of the
discovered knowledge for the structure–function analysis methods is not usually
addressed. Several researchers have studied the correspondence of sample size to
power for statistical tests such as the chi-square and Fisher exact tests of
independence,169 and compared the relative power of different statistical tests of
independence.170–173 In addition, simulations have studied the power of chi-square
analysis in sample spaces of much higher dimensionality, as one would expect to find
in many epidemiological studies.173–176 However, no closed-form power analyses exist
that can account for the simultaneous effects of image noise and registration error, in
addition to the characteristics of the statistical methods being employed.
One can use a simulator177 to not only test the scalability of mining methods, but
also evaluate different methods as a function of the number of samples needed, the
strength and complexity of associations, the spatial distribution of ROIs, and the
registration method used. A simulator can generate a large number of artificial
subjects and construct a probabilistic model of lesion-deficit or task-activation
associations. One can then model the error of a given registration method, apply it to
the image data, perform mining, and compare the generated associations with those
detected by the mining methods. The number of subjects required to recover the
known associations reflects the statistical power of the particular combination of
image-processing and statistical methods being evaluated.
 Data mining in brain imaging 379
4.3.1 Using a simulator
As a case study, we show results from the evaluation of the Fisher exact test for the
detection of lesion-deficit associations.177 The results quantify the sensitivity and
accuracy of the mining method as a function of the number of subjects in the sample,
the strength and complexity of the associations, and the errors that arise due to
imperfect registration.
Comparing the results of simulated analysis to known associations allows one to
quantify the performance of a mining method. For this study, the simulation para-
meters for the distributions were obtained from data collected as part of the Frontal
Lobe Injury in Childhood (FLIC)100 lesion-deficit study. Simulated lesions were
generated using distributions for the number, size, and location of lesions. Because
misregistration introduces noise in the form of false-negative and false-positive
associations, this source of error was modelled by assuming that it follows a 3-D
nonstationary Gaussian distribution. Registration error was estimated by measuring
the error on distinct anatomical landmarks on a number of subjects and then
interpolating the error in the rest of the brain. The lesion-deficit-association model,
with its conditional-probability tables and prior probabilities, describes the relation-
ships between structures and functions. In the case where structure and function
variables are categorical (normal vs abnormal), these associations can be modelled
using Bayesian networks (BNs)145 as covered in Section 3.3.2. To examine the effect of
the strength of the lesion-deficit associations on the ability of the mining methods to
detect them, Table 3 presents three cases corresponding to strong, moderate, and weak
associations. Thus, a strong association between a structure si and a function fj is
denoted by conditional probabilities p(fj = A| si = N) = 0, p(fj = A|si = A) = 1,
p(fj = N| si = N) = 1 and p(fj = N|si = A) = 0, where A means abnormal and N
normal. Moderate and weak associations were defined similarly. Nondeterministic
disjunctive interactions between more than one structure and a function were
modelled using a noisy-OR model.142
The prior probability of structure abnormality for each structure si , in each subject
pj , was calculated from fsi ;pj : the fraction of the volume of si that overlapped with lesions
for pj . The conditional probability p( si |fsi ;pj ) is expected to be a sigmoid function,
although a step function with an appropriate threshold is used for simplicity. Each
structure with at least 1% of its volume overlapping with lesions was labelled as
abnormal for that subject. For each pair of simulated subject and structure, the prior-
probability distribution was sampled and a binary vector for the structures was
generated. By instantiating the states of all structure variables of the BN, the

Table 3 Three cases of BNs considered in a simulator177

Case Association Conditional probabilities for functions

1 Strong 0/1
2 Moderate 0.25/0.75
3 Weak 0.49/0.51
380 V Megalooikonomou et al.

conditional probability for each function variable was determined by table lookup.
This probability was then used to generate the binary vector for the function variables,
and Fisher’s exact test of independence was applied to each structure-function pair.

4.3.2 Results from the evaluation of a mining system

In this section, we describe how a lesion deficit simulator can be used to determine
the number of subjects needed to discover the simulated lesion-deficit associations
represented by a Bayesian network, the strengths of associations, the number of
associations, the degree of the network (i.e. the number of structures related to a
particular function), and the prior probabilities for structural abnormalities. A
Bayesian network with sufficient complexity was used177 to demonstrate the use of a
simulator in reaching meaningful results regarding the performance of the Fisher
exact test and the effects of misregistration. Since the performance of any method for
detecting associations depends on the characteristics of the conditional-probability
tables, three cases (see Table 3) were examined to study this effect. The prior
probability of abnormality for each structure was set to 0.5 to allow testing the
behaviour of the Fisher exact test for the optimal value of the prior probability. To
generate the conditional-probability table for those function variables that were
related to more than one structure, a noisy-OR model was used. The threshold 0.001
was used for the p-value, since this gives a good trade-off between the number of
simulated associations and the number of false positives detected. Figure 11
demonstrates the dramatic effects of the different conditional-probability distributions
on the power of lesion-deficit analysis. As expected, more samples are required to
detect weaker associations.
The degree of the associations of the Bayesian network was found to have a much
greater effect on the performance of the Fisher exact test than the total number of
associations. This result implies that, for functions that are associated with many
structures, identification of structure–function associations is difficult and requires a
larger sample size. Figure 12(a) shows the performance of the Fisher exact test for
three networks of 20, 40, and 80 edges and of the same degree (4) for the moderate case
(i.e. case 2) of the conditional-probability tables. Figure 12(b) shows the effect of
increasing the degree of the network (the number of structures affecting a particular
function) while fixing the total number of edges using the moderate case of the
conditional-probability tables.
Figure 11(b) demonstrates the performance of the Fisher exact test for the three
cases of Bayesian network conditional probabilities (see Table 3) when the prior
probability of a given structure being abnormal is obtained from the simulated data
set. The number of edges that could actually be discovered is 55 (80%), since there
were 14 edges from structures that did not intersect any lesions. Comparing this figure
with Figure 11(a), in which uniform prior probabilities were used, more subjects are
required to recover all associations when data-derived prior probabilities are used
instead of uniform prior probabilities, as expected. Also as expected, the number of
subjects needed is inversely proportional to the smallest prior probability. The
detection of false-positive associations is due to the existence of associations among
neighbouring structures due to lesions that intersect more than one structure.
Additional false positives can be observed in cases where associations occur between
 Data mining in brain imaging 381

(a)

(b)

Figure 11 Evaluating a mining method. Performance of the Fisher exact test (p 0.001) for (a) uniform (0.5)
prior probabilities and (b) data-derived prior probabilities of structure abnormality, for the three strengths of
lesion-deficit associations from Table 3 that correspond to strong (case 1), moderate (case 2) and weak (case 3)
associations. The difference between the total number of associations detected and the number of true
associations detected is the number of false-positive associations detected for each case. The horizontal line in
(a) represents the total number of simulated edges (69) and in (b) represents the total number of simulated
edges that can be detected (55). Graphs from Megalooikonomou et al.177
382 V Megalooikonomou et al.

(a)

(b)

Figure 12 (a) Evaluating a mining method. Performance of the Fisher exact test (p 0.001) for BNs with degree
4 with 20, 40 and 80 edges. (b) Performance of the Fisher exact test (p 0.001) for BNs with 48 edges, and
with degree 4, 6, and 8. Graphs from Megalooikonomou et al.177
 Data mining in brain imaging 383

behavioural variables. On average the specific registration method used reduces the
number of associations discovered by 13% for the same number of subjects when
compared with perfect registration.

5 Concluding remarks

In this review we have presented data mining methods that have been or could be used
for knowledge discovery from brain images of different modalities along with other
clinical data. We have focused on the problems of: (1) finding associations between
structures and functions through task-activation and lesion-deficit studies, (2)
studying the morphological variability of brain structures and finding associations
with certain conditions, (3) classifying shapes of brain structures, including tree-like
structures such as nerve fibres and abnormalities such as tumours, and searching for
similarity, and (4) finding associations between gene expressions, morphology, and
function. We have presented results of applying mining methods to epidemiological
data that demonstrate detection of several clinically meaningful associations in
different studies. These methods can lead to interesting conclusions about the funct-
ional mapping of the human brain, the effect of lesions or other abnormalities in the
development of neurological and neuropsychological deficits, and the effect of certain
diseases and gene expressions on structural morphology and function.
Visualization can help reduce the inherently enormous search space in statistical
analysis. Exploratory analysis through the use of a statistic for many tests produces
reasonable results, although one has to deal with the multiple-comparison problem.
Voxel-based approaches show encouraging results, but are computationally intensive
and even more severely impacted by the multiple comparison (although the latter can
be addressed with clustering analysis). Statistical simulations show that more
advanced mining methods and large sample sizes are required to determine lesion-
deficit associations accurately, with reduced number of false positive associations.
Simulators can be used for verifying and comparing mining methods in brain
imaging. Their use is very important especially in determining the number of subjects
needed to detect all associations while reducing false positives. In particular, in lesion-
deficit analysis, simulators have shown that the number of subjects required to detect
all and only those associations in the underlying model (i.e. the ground truth) may be
in the thousands, even for strong associations, particularly if the spatial distribution of
lesions does not extend to all structures. The more one descends from the 0.5 level for
prior probabilities, the more difficult it becomes to discover associations. These results
underline the necessity of developing large image databases for the purpose of meta-
analysis of data pooled from multiple studies, so that more meaningful results can be
obtained. The testing procedure framework is very important, since it can be used to
characterize the power of methods for detecting multivariate associations while taking
into account the effects of registration and noise. Simulators can also be used in the
evaluation of new analysis methods, as well as in the study of the effect of different
registration and segmentation algorithms.
Existing mining algorithms are limited in that they typically assume data will
consist of individual numeric and symbolic features. We still lack effective algorithms
384 V Megalooikonomou et al.

for learning from data that is represented as a combination of various types (i.e.
multimedia data). Predictions based on the full medical record could potentially
achieve much greater accuracy than those that are limited to one data type. In
addition, prediction accuracy can be improved by inventing more appropriate features
to describe the brain data. We need new methods that actively generate optimal
experiments to collect the most informative data. Another obstacle is integrating data
from different investigators and analysing them jointly. Brain imaging data are
usually collected in a single database for a specific study and with a specific data
mining task in mind, so an additional important issue is interoperability and the
ability to learn from multiple databases.178 Also, the mining algorithms developed so
far tend to be fully automated and therefore do not allow active experimentation, i.e.
guidance from experts at key stages in the search for brain data regularities. Ideally,
human experts should be able to collaborate closely with a mining algorithm to form
hypotheses and test them against the data. In addition, mining methods need to be
able to scale to extremely large data sets. Research during the past few years has
already produced more efficient algorithms for such problems as learning association
rules2 and efficient visualization of large data sets.179 A closer integration of machine
learning algorithms into database management systems is also needed.

Acknowledgements
The authors wish to thank Christos Davatzikos, Eddie Herskovits, Christos
Faloutsos, Paul Thompson, David Isecke, Ling Cheng, and Tilmann Steinberg for
providing pictures, comments, and other helpful information. This work was
supported in part by the Ira DeCamp Foundation, NARSAD and New Hampshire
Hospital. Support was also provided by the Dartmouth Experimental Visualization
Laboratory (DEVLAB).

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Appendix A1: application of t-test in SPM

The t-test compares two groups of samples and determines whether there is a
significant difference; here the groups are MR signal readings during two different
states (conditions): one R state (rest or control) and one T state (test or task). Let xyz
denote a voxel (volume element) of a 3-D image and let N be the total number of
voxels. Then the 3-D images [rxyz;R ], [rxyz;T ] exist for each subject k. Let [
rxyz;k ] where

rxyz;k ¼ rxyz;k;Tÿ rxyz;k;R be the voxel-by-voxel subtraction picture of the differences in
392 V Megalooikonomou et al.

r between R and T. If all rxyz representing the brain in anatomically standardized

pictures can be regarded as normally distributed, it is possible to calculate a
descriptive t-test:
E
rxyz
t
rxyz ¼ rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
Var
rxyz
n
where the E
rxyz and Var
rxyz are the mean and variance of
rxyz , respectively:
1Xn
E
rxyz ¼
rxyz;k;T
n k

and
1 Xn ÿ
2
Var
rxyz ¼
rxyz ÿ E
rxyz
nÿ1 k

Appendix A2: use of the deformation function in analysis of morpho-

logical variability

A deformation function dðu; vÞ, is defined at each point ðu; vÞ of the atlas structure, S,
of interest. It measures the enlargement or shrinkage associated with the transforma-
tion from an infinitesimal region around a point in the atlas space to its corresponding
infinitesimal region in the subject space. If the point ðu; vÞ of the atlas space is mapped
to the point [Uðu; vÞ; V ðu; vÞ] in the subject space, then dðu; vÞ is defined by
dðu; vÞ ¼ detfr½Uðu; vÞ; V ðu; vފg, where r denotes the gradient of a vector function
and detð
Þ denotes the determinant of a matrix. Intersubject comparisons are made by
comparing deformation functions. Specifically, let [U1 ðu; vÞ], ½V1 ðu; vފ; . . . ;
½UN ðu; vÞ; VN ðu; vފ be the maps from the structure S of the atlas to the structure S
of each of the N subjects of a population. Let also Up ðu; vÞ and Vp ðu; vÞ be the average
of the N functions U1 ; . . . ; UN and V1 ; . . . ; VN , respectively:
X X
Up ðu; vÞ ¼ 1=N Ui ðu; vÞ; Vp ðu; vÞ ¼ 1=N Vi ðu; vÞ
I¼1;...;N I¼1;...;N

The average structure Sp of that population is defined as the collection of the points
where the atlas structure points are mapped:
Sp ¼ [ðu;vÞ2Sa ½Up ðu; vÞ; Vp ðu; vފ
where Sa is the collection of points belonging to structure S of the atlas. Let p ðu; vÞ be
the point-wise mean of the deformation function of the population:
X
p ðu; vÞ ¼ 1=N di ðu; vÞ
I¼1;...;N
 Data mining in brain imaging 393

where d1 ðu; vÞ; . . . ; dN ðu; vÞ are the deformation functions of the N subjects. Then the
difference between the two populations, denoted with subscripts 1 and 2, can be
measured for each structural region as an effect size180 defined as
eðu; vÞ ¼ ðp1 ðu; vÞ ÿ p2 ðu; vÞÞ=ðu; vÞ
where ðu; vÞ is the point-wise standard deviation of the two populations combined.

Appendix A3: generation of a Bayesian network from a database

Without loss of generality, we assume in this section that each variable is Boolean, i.e.
it represents a logical statement that is either true (T) or false (F). The problem of
generating the Bayesian-network structure that is most likely to have generated the
cases in the database D can be restated as
BSmax ¼ argmax PðBS jDÞ
Bs

where BSmax is the network structure (i.e. set of associations) we seek. Using Bayes’
theorem, we obtain
PðDj BS ÞPðBS Þ
BSmax ¼ argmax
BS PðDÞ
Since the prior probability of observing the data is constant for all models, the
problem reduces to solving
BSmax ¼ argmax PðDj BS ÞPðBS Þ
BS

Here, we describe an approach for generating a Bayesian network from a database,

based on the above equation.143 Although we will discuss the application of this
method to a lesion-deficit study the method can be applied to the more general
problem of finding associations. Let D be a database of lesion-deficit cases, let Z be the
set of discrete variables represented by D, and let BS represent an arbitrary Bayesian-
network structure containing just the variables in Z. In this section, we shall write as
though database D were generated by Monte Carlo sampling of a Bayesian network
with structure BS that is hidden from us, or, equivalently, from a multivariate
distribution with conditional-independence among variables determined by BS . The
primary goal is to use D to discover BS . The assumptions that explicitly delineate the
problem are: (1) the process that generated D is modelled as a Bayesian network
containing just the variables in Z; (2) cases occur independently, given a Bayesian-
network model; (3) cases are complete (not missing data); (4) the distributions f(BP |
BS ) are independent of each other; and (5) the second-order probabilities are uniform.
The application of assumption 1 yields
Z
PðBS ; DÞ ¼ PðDj BS ; BP Þf ðBP j BS ÞPðBS Þ d BP
BP
394 V Megalooikonomou et al.

where BP is a vector whose values denote the conditional-probability assignments

associated with Bayesian-network structure BS , and f is the second-order conditional-
probability density function over BP given BS . The integral is over all possible value
assignments to BP. Thus, the integration is over all possible Bayesian networks that
can have structure BS . The integral in the above equation is a multiple integral in
which the variables of integration are the conditional probabilities, BP, associated with
structure BS . Note that this formulation explicitly admits the concept of a prior-
probability distribution, P(BS ), over the possible Bayesian-network structures. One
can assume uniform priors over structures, or calculate these prior probabil-
ities.143,144,177
From these five assumptions Cooper and Herskovits derive an equation for
computing PðBS ; DÞ:
n Y
Y qi
ðri ÿ 1Þ! Y ri
PðBS ; DÞ ¼ PðBS Þ ÿ
Nijk !
i¼1 j¼1
Nij þ ri ÿ 1 ! k¼1

where n is the number of variables in D (or nodes in BS ), ri is the number of values

that node i can assume, qi is the number of different instantiations of the parents of
node i found in D, Nij is the number of cases in D with the parents of node i assuming
the jth value in the list i of their instantiations that are found in D, and Nijk is the
number of the Nij cases in D with node i assuming value k. This equation allows the
calculation of P(BS , D) using P(BS ) combined with enumeration over the cases in the
database. Maximizing P(BS , D) over all possible BS is equivalent to maximizing
P(BS |D) over all possible BS , which is the goal of this approach. Cooper and
Herskovits144 prove that this metric has polynomial computational complexity, and is
asymptotically optimal in terms of delineating all and only associations among the
variables in the underlying distribution. Because the number of possible associations
among the variables is more than exponential in the number of variables under
consideration, it is critical that this metric be computationally efficient, and that
heuristic search (e.g. simulated annealing or greedy search) be used.