U.S. patent application number 11/890286 was filed with the patent office on 2008-07-24 for method and apparatus for displaying information.
This patent application is currently assigned to Children's Medical Center Corporation. Invention is credited to Gabriel S. Eichler, Sui Huang, Donald E. Ingber.
Application Number | 20080174610 11/890286 |
Document ID | / |
Family ID | 32965438 |
Filed Date | 2008-07-24 |
United States Patent
Application |
20080174610 |
Kind Code |
A1 |
Ingber; Donald E. ; et
al. |
July 24, 2008 |
Method and apparatus for displaying information
Abstract
A method for displaying large amounts of information. The method
includes the steps of forming a spatial layout of tiles each
corresponding to a representative reference element; mapping
observed elements onto the spatial layout of tiles of
representative reference elements; assigning a respective value to
each respective tile of the spatial layout of the representative
elements; and displaying an image of the spatial layout of tiles of
representative elements. Each tile includes atomic attributes of
representative elements. The invention also relates to an apparatus
for displaying large amounts of information. The apparatus includes
a tiler forming a spatial layout of tiles, each corresponding to a
representative reference element; a comparator mapping observed
elements onto said spatial layout of tiles of representative
reference elements; an assigner assigning a respective value to
each respective tile of said spatial layout of representative
reference elements; and a display displaying an image of the
spatial layout of tiles of representative reference elements.
Inventors: |
Ingber; Donald E.; (Boston,
MA) ; Huang; Sui; (Boston, MA) ; Eichler;
Gabriel S.; (Cambridge, MA) |
Correspondence
Address: |
Kirkpatrick & Lockhart Preston Gates Ellis LLP;(FORMERLY KIRKPATRICK &
LOCKHART NICHOLSON GRAHAM)
STATE STREET FINANCIAL CENTER, One Lincoln Street
BOSTON
MA
02111-2950
US
|
Assignee: |
Children's Medical Center
Corporation
Boston
MA
|
Family ID: |
32965438 |
Appl. No.: |
11/890286 |
Filed: |
August 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11108623 |
Apr 18, 2005 |
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11890286 |
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10435660 |
May 9, 2003 |
6888543 |
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11108623 |
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60452857 |
Mar 7, 2003 |
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Current U.S.
Class: |
345/619 |
Current CPC
Class: |
G06T 11/60 20130101 |
Class at
Publication: |
345/619 |
International
Class: |
G09G 5/00 20060101
G09G005/00 |
Goverment Interests
GOVERNMENT RIGHTS
[0002] This invention was made with U.S. Government support under
Grant F49620-01-1-0564 awarded by the U.S. Air Force Office of
Scientific Research; Cooperative Agreement NAG2-1501 awarded by the
Ames Research Center of the National Aeronautics and Space
Administration (NASA); and Grant CA 55833-09 awarded by the
National Institute of Health (NIH). The government may have certain
rights in the invention.
Claims
1. A method of displaying a set of data comprising the steps of:
forming a spatial layout of tiles each corresponding to a
representative reference element in a mosaic; mapping observed
elements onto said spatial layout of tiles of representative
reference elements; assigning a respective value to each respective
tile of said spatial layout of representative reference elements;
and displaying an image of the spatial layout of tiles of
representative reference elements, wherein each tile comprises
atomic attributes of representative elements.
2. The method claim 1 wherein the step of forming said spatial
layout of tiles each corresponding to said representative reference
element in said mosaic comprises the steps of forming a self
organizing map.
3. The method of claim 2 wherein the steps of forming a self
organizing map comprise the steps of: a.) forming representative
reference elements; b.) matching an observed element to a
respective representative reference element to select a best unit
matching centroid; c.) adjusting the best unit matching centroid to
form an adjusted best unit matching centroid; and d.) iterating
steps b and c a plurality of times for each observed element.
4. The method of claim 3 wherein the step of matching said observed
element to said representative reference element comprises the step
of measuring the Euclidean distance between said observed element
and each representative reference element and selecting said
representative reference element having the least distance
Euclidean distance.
5. The method of claim 3 wherein the step of matching said observed
element to said representative reference element comprises the step
of measuring the correlation between said observed element and each
representative reference element and selecting said representative
reference element having the highest correlation.
6. The method of claim 3 wherein the step of adjusting the best
unit matching centroid comprises adjusting the value of the
representative reference element to form an adjusted best unit
matching centroid.
7. The method of claim 6 wherein the step of adjusting the best
unit matching centroid includes the step of adjusting neighboring
representative reference elements.
8. The method of claim 7 wherein the neighboring representative
reference elements are included within a boundary radius describing
the size of a neighborhood.
9. The method of claim 8 wherein the boundary radius decreases with
iteration.
10. The method of claim 7 wherein the step of adjusting the
neighboring representative reference elements comprises the step of
modifying the neighboring representative reference elements by an
adjustment strength which is a function of the distance from the
best unit matching centroid to the neighboring representative
reference element being adjusted.
11. The method of claim 10 wherein the adjustment strength
decreases with iteration.
12. The method of claim 1 wherein the step of assigning said
respective value to each respective tile of said spatial layout of
representative reference elements comprises assigning a color to
each respective tile in response to the value of the tile.
13. The method of claim 1 wherein the step of assigning said
respective value to each respective tile of said spatial layout of
representative reference elements comprises assigning a height to
each respective tile in response to the value of the tile in a
three dimension graph.
14. The method of claim 1 wherein the respective value of the
respective tile is a value associated with the respective reference
element.
15. The method of claim 1 wherein the step of assigning said
respective value to each respective tile of said spatial layout of
representative reference elements comprises assigning, to each
respective tile in response to the value of the tile, a property
selected from the group consisting of: symbol shape, size, hue and
pitch.
16. The method of claim 1 further comprising the step of repeating
the step of displaying an image of the spatial layout of tiles of
representative reference elements to form a motion image.
17. The method of claim 1 further comprising the step of
concatenating data comprising observed elements.
18. A method of displaying information comprising the steps of: a.)
normalizing data of said observed elements; b.) generating
reference centroids; c.) generating a map of said reference
centroids; d.) matching an observed element to a respective
reference centroid; e.) adjusting said respective reference
centroid and neighboring reference centroids within a neighborhood
radius; f.) iterating steps e and f, modifying the strength of
adjustment and neighborhood radius to form a plurality of adjusted
reference centroids; g.) matching each observed element to a
respective adjusted reference centroid of said plurality of
adjusted reference centroids; h.) assigning a respective value for
each adjusted reference centroid; i.) assigning a respective
graphic representation to each respective value; and j.) displaying
a mosaic of each graphic representation.
19. The method of claim 18 further comprising the step of iterating
step j to form a motion graphic.
20. The method of claim 18 further comprising the step of
concatenating data comprising observed elements prior to
normalizing the data.
21-37. (canceled)
Description
RELATED APPLICATIONS
[0001] The application is a continuation of prior application U.S.
Ser. No. 11,108,623, filed on Apr. 18, 2005, which is a
continuation of application U.S. Ser. No. 10/435,660, filed on May
9, 2003, which claims priority to and the benefit of provisional
application U.S. Ser. No. 60/452,857, filed on Mar. 7, 2003, and
assigned to the assignee of the instant application. The
above-identified applications are hereby incorporated by reference
herein. This application incorporates by reference U.S. utility
application Ser. No. 09/985,963, filed on Oct. 19, 2001, which
claims priority to provisional application U.S. Ser. No.
60/242,009, filed on Oct. 20, 2000, both of which assigned to the
assignee of the instant invention. Both utility application Ser.
No. 09/985,963 and provisional application Ser. No. 60/242,009 are
herein incorporated by reference.
FIELD OF THE INVENTION
[0003] The invention relates generally to the field of informatics
and more specifically to the field of informatic displays.
BACKGROUND OF THE INVENTION
[0004] The behavior of a large number of interacting elements in a
system is difficult to display, analyze and interpret. Many
techniques have been attempted to derive an ordered model from the
elements in such a system. An example of a system which produces
such a large amount of data is the genome. Not only may the genome
consist of a large number of genes (numbering in the tens of
thousands for the human) but many genes of an organism interact.
For example many genes exert control over other genes. That is many
genes either induce or raise the expression level of other genes or
inhibit or decrease the expression level of other genes. The act of
just displaying the genes of a genome and their interactions, never
mind analyzing such a large amount of data, is daunting. Since the
genes exert control on each other, they do not change their
expression levels independently, but instead form a genome-wide
network of interactions. Similarly, proteins and metabolites and
other cell constituents are part of a network of interactions. The
consequence of this mutual control between different genes or
molecules is that the dynamics of the molecular profiles are
constrained to certain coherent, recurring patterns.
[0005] Self Organizing Maps or SOMs have been used in an attempt to
group genes according to their expression activity versus time
profile. Under this technique, genes having similar expression
behavior are grouped together into clusters on a matrix of
behaviors. The output of this algorithm is essentially just the
information about individual genes with regard to their assignment
to one of these clusters. However, displaying these genes as a
matrix of expression behaviors provides a complicated array of
graphs that does not help significantly with the analysis of the
interactive gene behavior or with the interpretation of coherent
patterns that emerge in the displayed expression profiles.
[0006] Similarly, other currently used analysis techniques for gene
profiling, such as in hierarchical clustering, k-means clustering
or principal component analysis, group genes into a small number of
clusters relative to the total number of genes, and also fail to
visualize patterns within the overall gene profile.
[0007] In order to study the recurring patterns within genome-wide
expression or molecular profiles, it is necessary to monitor the
change of entire profiles at different times during a sequential
process, or in response to multiple variables, such as during the
longitudinal monitoring of multiple patients or of the biological
responses of cells or tissues following treatment with various
drugs. Such comparative time course analysis will generate data
volumes comprised of three dimensions: (i) the elements of the
molecular profile (e.g., the genes in gene expression profiles);
(ii) the time points at which the profile is measured and (iii) the
time course for each of the various processes studied. Existing
gene clustering techniques are generally not capable of
simultaneously monitoring multiple dimensions, and hence a new
method is required to visualize these global time-dependent changes
in gene expression profiles.
[0008] The present invention provides a method and apparatus to not
only group genes according to activity but also to display the
activity in such a way that reveals characteristic patterns in the
monitored profiles, hence visualizing the underlying relationship
between the genes that comprise the regulatory network. It also
provides a method to display the information of all three
dimensions--gene, time and process--simultaneously.
SUMMARY OF THE INVENTION
[0009] The invention relates to a method for displaying large
amounts of information. The method includes the steps of forming a
spatial layout of tiles each corresponding to a representative
element; matching observed elements onto the spatial layout of
tiles of representative elements; assigning a respective value to
each respective tile of said spatial layout of representative
elements; and displaying an image of the spatial layout of tiles of
representative elements. Each tile includes atomic attributes of
the representative elements.
[0010] In one embodiment the step of forming a spatial layout of
tiles includes the step of forming a self-organizing map. In
another embodiment steps of forming a self organizing map include
the steps of forming representative reference elements, selecting a
best unit matching centroid and adjusting the best unit matching
centroid to form an adjusted best unit matching centroid. In still
yet another embodiment the step of matching an observed element to
a representative reference element includes the step of measuring
the Euclidean distance between the observed element and each
representative reference element, and selecting the representative
reference element having the least distance.
[0011] The invention also relates to a method of displaying
information. The method includes the steps of normalizing the data
of observed elements; generating reference centroids, generating a
map of the reference centroids; matching an observed element to a
respective reference centroid and adjusting the respective
reference centroid and the neighboring reference centroids. The
method also includes the steps of iterating the above steps,
modifying the strength of adjustment and the neighborhood radius to
form a plurality of adjusted reference centroids, and matching each
observed element to a respective adjusted reference centroid. The
method also includes the steps of assigning a respective value for
each sample, assigning a respective graphic representation to each
respective value and displaying a mosaic for each sample. In
another embodiment the step of displaying is repeated to form a
motion graphic. In yet another representation the respective
graphic is 3-D representation.
[0012] The invention also relates to an apparatus for displaying
large amounts of information. In one embodiment, the apparatus
includes a tiler forming a spatial layout of tiles each
corresponding to a representative element; a matcher matching
observed elements onto said spatial layout of tiles of
representative elements; an assigner assigning a respective value
to each respective tile of said spatial layout of representative
elements; and a display displaying an image of the spatial layout
of tiles of representative elements. Each tile includes atomic
attributes of the representative elements.
[0013] In one embodiment the tiler includes a self-organizing map
processor. In another embodiment the assigner assigns a color to
each respective tile. In yet another embodiment the display is a
3-D display.
[0014] The invention also relates to an apparatus for displaying
data. In one embodiment the apparatus includes a normalizer
normalizing the data of observed elements, a reference centroid
generator generating a plurality of reference centroids and a map
of the reference centroids and a comparator matching an observed
element to a respective reference centroid. In another embodiment a
processor iteratively adjusts the respective reference centroid and
neighboring reference centroids to form a plurality of adjusted
reference centroids. The embodiment also includes a matcher
matching an observed element to a respective adjusted reference
centroid, a value assignor which assigns a respective value to each
sample and a graphics engine assigning a graphic representation to
each respective value and displaying a mosaic for each sample.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] These and other features of the invention will be better
understood by reference to the attached specification and drawings
of which:
[0016] FIG. 1 is a graphic representation of an embodiment of the
method of the invention used display gene activation;
[0017] FIG. 2 is a graphic representation of an embodiment of the
method used to generate the self organizing map of FIG. 1;
[0018] FIG. 3 is a graphic representation of the matching of gene
profiles to the self organizing map of FIG. 2.
[0019] FIG. 4 is a graphic representation of the results of an
embodiment of the invention used to observe gene expression as a
function of time and drug exposure.
[0020] FIG. 5 is a graphic representation of the results of an
embodiment of the invention used to observe gene expression as a
function of time and drug exposure that displays a change in cell
fate from a proliferative promyelocytic precursor cell to a
differentiated neutrophil.
[0021] FIG. 6a is a series of mosaic representations, as produced
by an embodiment of the invention, of gene expression in various
normal human tissue types from sixteen different subjects;
[0022] FIG. 6b is a series of mosaic representations, as produced
by an embodiment of the invention, of gene expression in various
human tissue types obtained from sixteen subjects; and
[0023] FIG. 6c is a series of mosaic representations, as produced
by an embodiment of the invention, of gene expression in various
prostate disease states, obtained from eleven human subjects.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0024] Referring to FIG. 1, for the purpose of simplifying the
explanation, the method of the invention is herein described using
the specific example of analyzing the expression of a large number
of genes, either from a number of tissue specimens 10, in response
to a variety of drugs 14 or a time course of specific drugs 16.
However this is for the purpose of example only and the method can
be used to display a large number of elements (in the example
shown, genes) either statically or over time. For example, the
information displayed could be a multitude of stocks as their
prices vary with time; telephone numbers used as a function of time
or any of a number of examples of systems having a large number of
elements.
[0025] In FIG. 1, we assume that there are six samples, generating
six gene expression profiles to be analyzed 18. In this example
there are potentially three possible scenarios as to the origin of
the samples and associated study question.
[0026] In the first scenario each sample represents a tissue
specimen (from different patients) that will be compared (one
through six) 10. No time course is involved. In the second scenario
, three drugs (A, B, and C) are compared; each drug being tested on
two patients. Again, no temporal monitoring is involved, only the
static outcome for each drug/patient is measured 14. In the third
scenario, the six samples are derived from monitoring two time
courses (A and B) with three time points (1, 2 and 3 hr) each. The
two time courses represent the response of a cell culture or
patient to two different drugs, Drug A and Drug B. The gene
expression in those tissues is examined through the use of a series
of six micro-arrays.
[0027] The technique is the same regardless of the scenario that
generated the samples. In the example shown the expression level of
sixteen genes is examined over a period of three hours after
exposure to drug A or B 16. These gene expression data are
collected (step 10) within a single matrix of data 22 including all
the data from all the microarrays. Importantly, even if the samples
represent time courses from independent experiments or different
patients, as is the case with the third example, they are entered
in the same data matrix. This concatenation of data, although
counterintuitive, is essential to permit the invention to function
when analyzing more than one sample class. Specifically, it enables
the comparison between multiple time courses with respect to the
individual elements (genes) and the patterns in the profile, in
response to different perturbations.
[0028] This concatenated data matrix is then used to generate (step
14) a plurality of reference centroids on a spatial layout against
which the observed gene expression values (element values) are
compared. In this example the reference centroids (A through I) are
generated using a Self Organizing Map 26 (SOM) but any number of
optimization methods that can generate centroids and place them on
a layout that minimizes differences between neighboring centroids
may be used. Alternative methods include, for example, energy
minimization algorithms and force displacement algorithms.
[0029] Referring to FIG. 2, to use a Self Organizing Map or SOM,
the SOM must be trained against the set of existing data in order
to generate the spatial layout of reference centroids. This
training is accomplished by initially developing a set of reference
centroids. Each reference centroid contains a list M of expression
values, one for each of the M samples. In FIG. 1, there are six
samples, thus the reference centroid is a list that contains 6
values. Every value of the reference centroid represents the value
of a single gene in one sample, and this value is referred to as an
atomic value, since it is associated with one sample and one
centroid. In this example, a three by three grid 28 of nine
reference centroids (A-I) is first created using random numbers to
generate the nine profiles (step 18). The optimal total number of
reference centroids (total number of tiles per mosaic grid) can be
determined empirically by the user and depends on the particular
structure of the data. The grid size corresponds to the resolution
of the analysis. The larger the grid (more tiles), the fewer
average number of genes per tile and the finer grained the
resolution. On smaller grids (fewer tiles) more genes are assigned
to a tile and a `blurry`, `pixelated` resolution will result.
[0030] In the analysis of gene expression data obtained in
experiments with 10 to 100 sample microarrays, containing 1000 to
60,000 genes, the total number of reference centroids is typically
100-3000. The grid shape is preferably not a perfect square grid,
in order to allow the mosaic image to orient itself properly on the
mosaic. For example, for a grid with 600 centroids, one may chose a
grid of 20 by 30 tiles. One method which can be used to determine
the optimal grid size is to first choose a desired average number
of genes assigned to each tile, J, and then to divide the total
number of genes by J. J is typically within the range of 1 to 15
genes however, this number may be varied as desired.
[0031] Of the set of genes (one through sixteen) in the array 22,
one gene (in this example gene nine) is randomly selected (step 22)
and its time course or expression graph 32 is compared (step 26) to
each of the centroids (A-I) of the set of reference centroids 28
until the best matching unit centroid (BMUC) is found (in this
example reference centroid C). Which reference centroid is the best
matching unit centroid or BMUC may be determined by any number of
means including the minimum Euclidean distance between the gene
expression graph and the reference centroid. Other measures of the
best fit may include the Pearson Correlation between the gene
expression graph 32 and the reference centroid graph (C); the use
of common sets or the angular distance, to name but a few.
[0032] Once the BMUC is found the BMUC is adjusted (step 30) to
bring it closer to the shape of the gene expression graph 32. The
BMUC 36 is not adjusted to exactly match the gene expression graph
but instead to be closer to it by a certain amount (referred to as
the strength of the adjustment). In the example shown, the first
adjustment 36 is made to bring the BMUC to within eighty percent of
the difference between the BMUC and the gene expression graph 32.
The resulting graph is an adjusted BMUC C' 40 which looks more
similar to the gene expression graph 32. Next the neighboring
reference centroids (B, E and F) 44 are also adjusted (step 34) to
match the gene expression graph albeit to a lesser strength of
adjustment (in this example sixty percent). The resulting adjusted
neighboring centroids are B', E' and F' 44'.
[0033] Although only nine centroids (A-I) are shown in this
example, in an actual application potentially thousands of cells
would appear in the array. The distance from the cell of interest,
in this case (C'), to the cells in the neighborhood being adjusted,
in this case B, E, F, is termed the radius and the distance to the
furthest cells being adjusted is the boundary radius. In the
example shown here the boundary radius is one, but in an actual
case it would extend out to many cells. The radius will affect the
patterns generated. A larger radius will create a more rigid map,
i.e. large variations in activation of neighboring tiles will not
be correctly displayed by the output mosaic. A radius which is too
small will fail to create visually coherent mosaics and clearly
defined neighborhoods of similarly behaving genes. The user must
find an appropriate value in between these two extremes. Typically,
the initial radius is set to 30% of the map's smallest dimension.
Therefore, a map which is 45 by 50 will have a radius of roughly
14.
[0034] The strength of adjustment for each cell up to the boundary
radius varies as a function of the radius value. The strength of
adjustment function may be linearly decreasing with increasing
radius or may take on some other function, set as exponentially
decreasing.
[0035] In this example, the only neighboring centroids adjusted are
immediately adjacent to the BMUC. So in the example shown the
radial distance is one and the strength of adjustment is sixty
percent. Again, in a real experimental situation, as the radial
distance is extended further from the BMUC, the strength of
adjustment would be decreased. So for example at a radial distance
of two the strength might be only forty percent and at a radial
distance of three the strength might be only thirty percent and so
on.
[0036] Next another gene is randomly chosen (step 38) and the above
described steps repeated. This iteration occurs many times using
all the genes in the set over and over again. At each iteration the
strength of adjustment for a given radius from each BMUC is
decreased. Thus, in the example shown, at a radius of 1 the
strength of adjustment was 80%, for the first iteration from the
first BMUC and would be reduced for a subsequent BMUC to, for
example, 78%, at a radius of one. Thus the strength of adjustment
is decreased over and over again allowing the profile in each of
the cells to converge to a final value. In this example the process
is iterated 10,000 times. Once all the iterations have taken place,
the SOM is considered to be trained. Once the SOM has been trained
the result is a set of adjusted reference centroids (A'-I') (FIG.
3). Because of the rapid convergence in the SOM algorithms, it is
usually sufficient to run the SOM for a number of iterations equal
to ten times the total number of genes in the input data matrix.
Convergence is tested by increasing the number of iterations.
Convergence is achieved when increasing the number of iterations
does not significantly change the output mosaic patterns based on
visual inspection.
[0037] Referring now to FIG. 3, at this point each of the genes
(one through sixteen) are compared against each of the adjusted
reference centroids (A'-I') and grouped according to their best fit
to one of the adjusted reference centroids (A'-I'), similar to as
was done during the generation of the adjusted reference centroids
(A'-I'). In the example shown, genes one, five and sixteen cluster
in adjusted reference centroid A'; genes two, four and seven
cluster in adjusted reference centroid F' and so on. In some cases,
the adjusted reference centroid, for example adjusted reference
centroid E', will have only one gene in the cluster (in this
example gene three). At this point in the process all the genes are
assigned to an adjusted reference centroid and listed in a gene
assignment list (Table 1). In addition a correspondence table
(Table 2) contains the expression values corresponding to each of
the adjusted reference centroids at each point in time. The array
of adjusted reference centroids is called a mosaic and the location
of each centroid in the mosaic is a tile.
[0038] However, since each adjusted reference centroid is a vector
containing the centroid expression values of the assigned genes in
all the samples (in the example of FIG. 1 there are six samples),
it cannot be easily visualized. Thus, the invention requires that
each adjusted reference centroid is split back into its atomic
values as described above reflecting the value of the assigned
genes in each of the samples. The atomic values representing the
same sample X in all the adjusted reference centroids thus can be
assigned to the tiles. The tiles with associated atomic values then
form the mosaic that represents that sample X. (FIG. 1, Table 2 and
Table 3) By repeating the procedure for each sample, one obtains
one mosaic for each sample 64
[0039] It is important to remember that genes having similar
expression profiles are grouped together in an adjusted reference
centroid tile and will have expression profiles similar to but not
necessarily identical to the profile of the adjusted reference
centroid at each point in time, as shown for example by gene 8
being matched to tile H'.
[0040] It is possible to display the values in the adjusted
reference centroids or tiles at each point in time in several ways.
In one embodiment, each value or range of values may be assigned a
color, representing an atomic value of the tile. For example the
value three in the example shown can be assigned the color blue;
the value four can be assigned the color green and so on. As a
result, in this example, for values corresponding to the first hour
of drug A 60, (listed in Table 2) adjusted reference centroids B',
D', E' and F' which have a value of 3 will be colored green, while
adjusted reference centroids C' and H' which have a value of 4 will
be colored yellow.
[0041] Similarly, for values corresponding to the second hour of
drug A, adjusted reference centroids A', C' and G', which now have
a value of 3, will be colored green while adjusted reference
centroids B' and E', which now have a value of 4, will be colored
yellow. By displaying the values of the adjusted reference
centroids at each point in time (drug A one hour, drug B two hours
etc.) on the centroid location map (Table 3) the result is a series
of centroid maps 64, each corresponding to a different time value.
If these maps are displayed sequentially a motion graphic is
generated which shows the centroids changing color with time as the
centroid value changes.
[0042] In this example, the tile of the mosaic represent atomic
gene expression values, i.e. each mosaic is one time point taken
from a time course consisting of many time points. The tiles
however can represent anything which is, or can be represented by,
a single numeric value. For example, one may wish to display
information about the tiles and the number of genes assigned to
them, rather than just the expression level of the tile.
[0043] Although this example has been described with various colors
corresponding to various values of the reference centroids, other
display methods are possible. For example various symbols can be
used to denote various values instead of color. Alternatively if a
3-D graph is used, the height of the block representing each tile
can represent a given value. It is also possible to have tones
represent the various centroids, such that by placing a cursor over
the centroid of interest, the tones generated over time will be
indicative of the changes to the values of the centroid over time.
In general the means for displaying the results are limited only by
the imagination of the designer.
[0044] Further, although each gene profile in this example is
matched to the adjusted reference centroid based upon the
corresponding profile of the centroid, what can be displayed as a
result of this match is not so limited. Thus, in this example,
although gene expression values were used to train the reference
centroids and match the genes to the reference centroids, any
property of the gene or of the centroid can be then displayed. So
in this example, once the genes have been mapped to the tiles,
other attributes of the genes can be displayed that were not used
in developing the spatial layout of the matrix.
[0045] For example, one can display the number of genes assigned to
each centroid to produce a density map. Gene attributes that can be
mapped onto the tile, in addition to the expression level, include
but are not limited to: membership to certain gene function classes
(gene ontology), to promoter sequence clusters, phenoclusters, the
expression level of the protein encoded by the corresponding gene,
or parameters from its position in the interactome, such as
connectance or centrality.
[0046] FIG. 4 is an example of the result of the method used to
display the time course of gene activation in living cells exposed
to various drugs or molecules, including CD40L, Anti-Ig,
Terbutaline, Prostaglandin (PG) E, and Stromal derived factor
(SDF)-1. In this case, about 13,000 genes were clustered into a
rectangular mosaic grid with 2256 tiles comprised of 47 columns by
48 rows. It is immediately visible, even without quantitative
analysis that similar patterns of gene expression profiles are
activated after 4 hrs exposure to CD40L and Anti-Ig on the one
hand, and to Terbutaline, SDF-1, and PGE on the other, indicating
two distinct types of molecular mechanism that are utilized by
these chemical agents. Note that the second group of ligands are
known to similarly activate G-protein coupled receptors and hence,
in fact do share a common molecular mechanism of action.
[0047] By analyzing how gene expression profiles change over time,
it is also possible to identify major shifts in the "state-space"
(a high dimensional space in which each gene represents a
dimension) that may be indicative of attractor switches (a
translocation of the gene expression in state space from one stable
region to another mutually exclusive region) within the network.
This would correspond to a significant all-or-none change in the
functional activity of the entire network, as occurs during major
changes in cell phenotype or fate, including switches between
growth, apoptosis, and differentiation. For example, FIG. 5 shows
two parallel time courses of HL60 cells treated with two distinct
drugs, DMSO and ATRA. Both of these agents are known to cause
terminal differentiation of HL60 cells into neutrophils. Major
changes of both mosaics at 18-24 hr indicate a shift in state
space, possibly associated with an attractor switch. This state
space shift is quite distinct in the two processes, as evidenced by
the disparate mosaic patterns at this time point. However,
subsequent mosaics (48h -144 h) suggest that the responses converge
in state space, since the overall mosaic patterns become more
similar again. This indicates that the terminal differentiated
state is an attractor state of the regulatory gene network. This
signature of an attractor switch at 18-24 hr may be used to screen
for chemical agents that produce distinct phenotypic responses
without having to wait until the end of the entire process.
[0048] It is also possible to compare gene expression profiles from
similar tissues taken from various individuals to visualize which
genes are characteristically activated in the same tissue types and
hence provide a diagnostic read-out of tissue type. In FIG. 6a,
gene expression profiles of about 7000 genes were generated for
samples of various normal human tissues from two donors per tissue
type and the resulting gene expression data graphically displayed
according to the teachings of the invention. As can be readily
seen, the graphic representations of the tissue type from both
individuals are similar for the same tissue type but are different
between tissue types. This indicates that the graphic display as
produced by the invention can be used to automatically determine
tissue type from gene expression information.
[0049] The visualization of tissue data can also be used to
diagnose diseased tissues. For example gene expression profiles may
be obtained from tumor of the same organ in different individuals.
These profiles may be compared to identify a tumor-specific gene
profile pattern, and to determine from which tissues the tumors
arose by comparing their gene expression patterns with profiles
from various normal tissue types. In FIG. 6b, gene expression
levels of 12626 genes were visualized using the present technology
in a human tumor and 3 different types of normal tissues (1,2, and
3) that were obtained from sixteen individuals. Note first that the
gene expression patterns within each group of the three tissue
types and the tumor are similar. As can be seen, tissue type 1 has
a triangular pattern of expression extending from the upper left to
the lower right and upper right corners of the grid. Tissue type 2
has substantially a horizontal pattern of expression. Tissue type 3
has an expression pattern which is substantially a vertical pattern
of expression. When the expression patterns for the tumors are
compared with these three tissue types, it is seen that the tumor
also has an expression pattern that extends diagonally from the
upper left to the lower right. Potentially this may imply that the
tumors have arisen from tissue type 1 and that the deviations in
gene expression from the gene expression in tissue type 1 may be
indicative of the tumor state.
[0050] In addition it is possible to classify or stage tumors
according to their profile. The tumors shown in FIG. 6b are the
same type of tumor as indicated by their generally similar
profiles. Similarly, Tissue types 1, 2 and 3 each display patterns
that are characteristic for their type. It is therefore possible to
distinguish various tissues and tumors visually using this
technique. In FIG. 6c, gene expression profiles of about 9000 genes
were generated for samples of prostate tissue removed from a normal
region of a gland that also contains a tumor, benign prostatic
hyperplasial tissue, prostate cancer tissue and metastatic prostate
cancer tissue. Again the resulting gene expression data graphically
are displayed according to the teachings of the invention. As can
be seen, the mosaic representations of the four prostate tissue
types not only vary between the normal and the diseased tissues,
but the patterns in the diseased tissues are signatures of the type
and stage of disease. This means that the graphic representations
generated by the invention can be used to provide a means for the
automated diagnosis of tissue disease state. Such a diagnosis based
upon the graphic representation of the invention will lead to low
cost screenings of patients and rapid identification based on gene
profiles without a requirement for gene identification or
clustering.
[0051] The program used to perform the functions described is also
capable of providing additional information to the user. So for
example by clicking on a tile in the mosaic all the genes
associated with that tile are listed. By selecting one of those
genes, the program is able to link to other databases to provide
information about the gene, gene products, disease states to name
but a few.
[0052] As discussed at the beginning of this specification, the
examples discussed herein are related to gene expression levels.
However, the technique may be applied to other large amounts of
data, for example, financial data such as in the stock market. In
this embodiment individual stocks take the place of genes and the
stock price of the stock takes the place of the gene expression
level of the gene. The analyses would proceed as before watching
groups of stocks rising and falling in value just as we saw groups
of genes being turned on or off. Clusters of stocks in the same
industry may be expected to rise and fall together with news
affecting the entire industry. Conversely a stock which is affected
because of news specific to its underlying company may be seen to
deviate from the industry cluster over time.
[0053] Similarly, intelligence gathering may utilize the present
invention in order to search for patterns of communication which
might indicate some form of threat. For example, one could examine
phone call patterns of designated individuals using the number
called, duration of call, or frequency of calls as an attribute for
each member of a phone network. Groups of individuals who are
interacting would show clustering and the increase in call length
or frequency could be related to some form of threat, just as the
amount of communication or "chatter" is used by the intelligence
agencies to determine potential threat levels at present. In
addition, it may be possible to identify critical "nodes" from
which most information flows outwards (e.g., as would be expected
from leaders of a terrorist cell) and to discriminate them from
receivers or followers. Most importantly, this technology can
identify major shifts in the "state-space" that are indicative of
attractor switches within the network; this would correspond to a
significant all-or-none change in the functional activity of the
entire network, as one might expect before a major terrorist
incident. Note that this is distinct from the level of activity
within all of the individual connections, as is currently used in
information gathering.
[0054] The invention may be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The foregoing embodiments are therefore to be considered
in all respects illustrative rather than limiting on the invention
described herein. Scope of the invention is thus indicated by the
appended claims rather than by the foregoing description, and all
changes which come within the meaning and range of equivalency of
the claims are intended to be embraced therein.
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