U.S. patent application number 11/103199 was filed with the patent office on 2005-09-22 for fast microarray expression data analysis method for network exploration.
Invention is credited to Kanevsky, Valery, Vailaya, Aditya.
Application Number | 20050209838 11/103199 |
Document ID | / |
Family ID | 25115771 |
Filed Date | 2005-09-22 |
United States Patent
Application |
20050209838 |
Kind Code |
A1 |
Kanevsky, Valery ; et
al. |
September 22, 2005 |
Fast microarray expression data analysis method for network
exploration
Abstract
A method for performing network reconstruction is provided. The
method includes the steps of selecting a predictor set of features,
adding a complement to the predictor set based on a quality of
prediction, checking to see if all of the features of the predictor
set are repeated, and then removing one feature from the predictor
set. The algorithm and method repeat the steps of adding a
complement, checking the predictor set and removing a feature until
the features of the predictor set are repeated. If the features of
the predictor set are repeated, the algorithm and method
terminate.
Inventors: |
Kanevsky, Valery; (San
Carlos, CA) ; Vailaya, Aditya; (Los Altos,
CA) |
Correspondence
Address: |
AGILENT TECHNOLOGIES, INC.
Legal Department, DL429
Intellectual Property Administration
P. O. Box 7599
Loveland
CO
80537-0599
US
|
Family ID: |
25115771 |
Appl. No.: |
11/103199 |
Filed: |
April 11, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11103199 |
Apr 11, 2005 |
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09779240 |
Feb 8, 2001 |
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6909970 |
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Current U.S.
Class: |
703/11 ;
706/11 |
Current CPC
Class: |
G01N 2500/00 20130101;
G16B 40/00 20190201; G16B 25/00 20190201; G01N 33/6803 20130101;
G01N 33/57426 20130101; G16B 25/30 20190201 |
Class at
Publication: |
703/011 ;
706/011 |
International
Class: |
G06G 007/48; G06G
007/58; G06F 017/20 |
Claims
What is claimed is:
1. A method of network reconstruction comprising: (a) selecting a
target; (b) selecting a predictor set of features; (c) adding at
least one complement to said predictor set based on a quality of
prediction; (d) checking to see if all of said features are
repeated; and (e) removing at least one feature from said predictor
set; and as a result of performing each of steps (a)-(e) at least
once, reconstructing a network.
2. A method as recited in claim 1, wherein said target can be
changed and subsets of targets can be formed for predicting other
associated predictor sets of features.
3. A method as recited in claim 1, further comprising repeating
steps (e), (c) and then (d) until determined in step (d) that all
of said features of said predictor set have been repeated k times
in a row, wherein k corresponds to the number of features in the
predictor set.
4. A method as recited in claim 3, wherein said predictor set of
features is compared to other associated predictor sets to
determine associated pathways that are used in network
reconstruction.
5. A method as recited in claim 3, wherein said predictor set of
features is compared to other non-associated predictor sets to
determine associated pathways that are used in network
reconstruction.
6. A method a recited in claim 3, wherein said predictor set is
used in determining clusters.
7. A method as recited in claim 3, wherein said k features of the
predictor set are ordered; and wherein said feature that is removed
from said predictor set is the first feature in the ordered
predictor set.
8. A method as recited in claim 1, wherein said selecting step
comprises: selecting k-1 number of features at random, wherein k is
a number greater than 1.
9. A method as recited in claim 1, wherein said features of said
predictor set are selected in a defined order.
10. A method as recited in claim 1, wherein said feature that is
removed from said predictor set in step (d) is the earliest feature
defined in the ordered predictor set.
11. A method as recited in claim 1, wherein the predictor set and
target are vectors in M-dimensional space, wherein M is a number
greater than or equal to 1.
12. A method as recited in claim 1, wherein said selected predictor
set has a size of between 1-1000 features.
13. A method as recited in claim 1, wherein said steps of selecting
and adding are performed by a processor-based device using a first
algorithm, and wherein said checking step is performed by a
separate algorithm.
14. The method of claim 1 wherein said selecting step comprises
selecting k-1 features associated with said target to include in
said predictor set, wherein k is a number greater than 1.
15. The method of claim 14 wherein said adding step comprises
adding a complement to said k-1 features to form a predictor set of
k features.
16. The method of claim 15 wherein said checking step comprises
checking to see if all of said k features of said predictor set
have been repeated k times in a row.
17. The method of claim 16 wherein said removing step comprises: if
determined in step (d) that all of said k features of said
predictor set have not been repeated k times in a row, removing a
feature from said predictor set in step (e) and returning to step
(c).
18. The method of claim 17 further comprising: (f) if determined in
step (d) that all of said k features of said predictor set have
been repeated k times in a row, then determining such predictor set
as a best predictor set of k features for predicting the presence
of said target.
19. The method of claim 18 further comprising: ordering the k-1
subset of features in a list.
20. The method of claim 19 wherein said adding said complement to
said subset comprises: adding said complement to one end of said
list.
21. The method of claim 20 wherein said removing said feature from
said predictor set comprises: removing said feature from the other
end of said list.
22. The method of claim 18 further comprising: determining whether
the determined best predictor set of k features for predicting the
presence of said target satisfies a predetermined threshold for
quality of prediction.
23. The method of claim 22 wherein if determined that the best
predictor set of k features for predicting the presence of said
target does not satisfy said predetermined threshold, then
incrementing the value of k.
24. The method of claim 23 further comprising: repeating steps
(a)-(f) for the incremented value of k.
25. The method of claim 22 if determined that the best predictor
set of k features for predicting the presence of said target does
not satisfy said predetermined threshold, performing the following:
(g) selecting the determined best predictor set of k features; and
(h) adding at least one complement feature to said k features to
form a new predictor set of k+1 features.
26. The method of claim 25 further comprising: (i) checking to see
if all of said k+1 features of said new predictor set have been
repeated k+1 times in a row; if determined in step (i) that all of
said k+1 features of said new predictor set have not been repeated
k+1 times in a row, removing at least one feature from said new
predictor set and returning to step (g); and (k) if determined in
step (i) that all of said k+1 features of said new predictor set
have been repeated k+1 times in a row, then determining such new
predictor set as a best predictor set of k+1 features for
predicting the presence of said target.
27. The method of claim 26 further comprising: determining whether
the determined best predictor set of k+1 features for predicting
the presence of said target satisfies said predetermined threshold
for quality of prediction.
28. The method of claim 1 wherein each of said features comprises
corresponding measurement data.
29. The method of claim 1 wherein said target is a multiple
dependency.
30. The method of claim 1 wherein said target is an associated
pathway.
31. Computer software, embodied on a computer-readable medium, and
operable for performing network reconstruction, comprising an
algorithm that performs the steps of: (a) selecting a target; (b)
selecting a predictor set of features; (c) adding a complement to
said predictor set based on a quality of prediction; (d) checking
to see if all of said features are repeated; and (e) removing one
feature from said predictor set; and as a result of performing each
of steps (a)-(d) at least once, reconstructing a network.
32. Computer software as recited in claim 31, wherein any of said
steps of said algorithm are user defined.
33. Computer software as recited in claim 31, wherein any of said
steps of said algorithm are software defined.
34. A method as recited in claim 31, further comprising repeating
steps (e), (c) and then (d) until determined in step (d) that all
of said features of said predictor set have been repeated k times
in a row, wherein k corresponds to the number of features in the
predictor set.
35. The method of claim 34 wherein said removing step comprises: if
determined in step (d) that all of said k features of said
predictor set have not been repeated k times in a row, removing a
feature from said predictor set in step (e) and returning to step
(c).
36. The method of claim 35 further comprising: (f) if determined in
step (d) that all of said k features of said predictor set have
been repeated k times in a row, then determining such predictor set
as a best predictor set of k features for predicting the presence
of said target.
37. A system for performing network reconstruction, comprising: (a)
a computer; and (b) computer software, embodied on a
computer-readable medium, and executable by said computer for
performing network reconstruction according to the steps of: (i)
selecting a predictor set of features; (ii) adding a complement to
said predictor set based on a quality of prediction; (iii) checking
to see if all of said features are repeated; and (iv) removing one
feature from said predictor set.
38. A method as recited in claim 37, further comprising repeating
steps (e), (c) and then (d) until determined in step (d) that all
of said features of said predictor set have been repeated k times
in a row, wherein k corresponds to the number of features in the
predictor set.
39. The method of claim 38 wherein said removing step comprises: if
determined in step (d) that all of said k features of said
predictor set have not been repeated k times in a row, removing a
feature from said predictor set in step (e) and returning to step
(c).
40. The method of claim 39 further comprising: (f) if determined in
step (d) that all of said k features of said predictor set have
been repeated k times in a row, then determining such predictor set
as a best predictor set of k features for predicting the presence
of said target.
41. A method of network reconstruction comprising: selecting k-1
subset of features associated with a target; ordering the k-1
subset of features in a list; adding to one end of the list a
complement feature to form a predictor set of k features;
determining whether the features of the predictor set have appeared
k consecutive times; if the features of the predictor set have not
appeared k consecutive times, then removing a feature from the
other end of the list; if the features of the predictor set have
appeared k consecutive times, then determining that the predictor
set is a best predictor set of k features for predicting the
presence of said target; and using the determined best predictor
set of k features for predicting the presence of said target.
42. The method of claim 38 further comprising: adding a second
complement feature to the one end of the list.
43. The method of claim 38 further comprising: repeating said
adding, determining, and removing steps until said determining step
determines a predictor set of features that have appeared k
consecutive times.
44. The method of claim 41 further comprising: using the determined
best predictor set of k features to determine the association of
multiple dependencies.
45. A method of network reconstruction comprising: (a) selecting a
subset of (k-x) features associated with a target, k being a number
greater than 1 and x being a number greater than 0 and less than k;
(b) adding x complement features to said subset to form a predictor
set of k features; (c) checking to see if all of said k features of
said predictor set have been repeated k times in a row; (d) if
determined in step (c) that all of said features of said predictor
set have not been repeated k times in a row, removing at least one
feature from said predictor set and returning to step (b); and (e)
if determined in step (c) that all of said features of said
predictor set have been repeated k times in a row, then determining
such predictor set as a best predictor set of k features for
predicting said target.
46. The method of claim 45 further comprising: using the determined
best predictor set of k features to determine the association of
multiple dependencies.
47. The method of claim 45 wherein if determined that using the
best predictor set of k features to determine the association of
multiple dependencies does not satisfy a predetermined quality of
prediction threshold, then incrementing the value of k.
48. The method of claim 45 wherein said target is a multiple
dependency.
49. The method of claim 45 wherein said target is an associated
pathway.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of co-pending
and commonly assigned U.S. patent application Ser. No. 09/779,240
entitled "FAST MICROARRAY EXPRESSION DATA ANALYSIS METHOD FOR
NETWORK EXPLORATION", the disclosure of which is hereby
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The micro-array was developed in 1995 to measure gene data
in a massively parallel fashion. Since that time a significant
increase in the amount of data per experiment has occurred (See
http:/www-binf.bio.uu.nl.- about.dutilh/gene-networks/thesis.html).
In the case of gene exploration, this extensive data is important
for use in assessing genes and their influence on expressed states
in organisms. In particular, it is necessary to assess the function
and operation of a particular gene; a gene being defined as a
prescribed area on a nucleic acid molecule that is necessary for
the production of a final expressed phenotype of an individual. On
a more complex and broader scale, the interaction network is also
of interest due to its influence in regulating higher cellular,
physiological and behavioral properties. Recent attempts are being
made to reconstruct the precise interaction network or its
fragments based on large-scale array experiments for a
condition-specific database, e.g., melanoma (Bittner et al., 2000).
The critical first step in these efforts is to find the smallest
subset of (predictors), within a desirable degree of precision,
related to an arbitrary target. Based on such set of predictors,
computed for every target of interest, it is possible to find the
smallest set that can explain or predict behavior of any target in
terms of expression. In the case of genes, finding the smallest set
to predict a prescribed behavior could be a very complicated and
arduous task given the massive amount of data that results from
analyzing a complete organism's genome.
[0003] Most important to scientists is the ability to select a
minimal cardinality set that can represent a whole set of expressed
information. In the pattern recognition literature, this is known
as feature selection or dimensionality reduction, depending on the
context.
[0004] The issue at hand now is a question of mathematics and
computation rather than pure biology. In particular, the specific
problem at focus has been addressed from a computational
standpoint. A number of algorithms can be applied from other fields
and areas of study to help solve this arduous task. The specific
problem at focus, from a computation standpoint, is to find the
best (with respect to a given quality of function) k-tuples, from a
set of n features, for many values of k. One method to find the
best k-tuple predictor subset is to conduct an exhaustive search
through all possible k-tuples. Although this approach always leads
to the best solution, it becomes intractable for even moderate
values of k (the computational time grows exponentially with
k).
[0005] Also important to bio-informatics will be the methods
developed for pattern recognition. In the context of pattern
recognition, machine learning, data mining and their applications
to various subject areas, e.g., medical diagnostics, manufacturing
test design, image recognition etc., a similar problem of subset
selection, known as feature selection is important. A number of
approaches have been proposed and designed to address these
problems or issues. The approaches include and are not limited to,
sequential (backward and forward) search techniques, floating
search techniques and genetic or protein algorithms. However,
methods based on the sequential search techniques suffer from the
nesting effect, i.e., they overlook good feature sets consisting of
individually poor quality features. A second method called the
floating search methods (Pudil et al., 2000; Somol et al., 2000)
attempt to avoid the nesting problem by successively adding the
best and removing the worst subsets of features from the candidate
set of features. This introduces an exponential complexity in the
search when the size of a subset grows. A significant drawback of
these methods is that they become slow for large dimensional data
sets as is the case with biological expression data. Genetic or
biological algorithms also do not have well defined stopping
criteria and, in principle, can be exponentially complex.
[0006] Most importantly, the above methods and algorithms are
intended to be applied in the field of array data processing to
enable computationally efficient searches for the smallest subset
of features that predict a target's expression levels within a
given level of confidence or accuracy.
[0007] It would, therefore, be desirable to develop a method and
algorithm that determines "good" solution sets with high
probability in linear time, with respect to total number of
features in a predictor set. For this reason, "sequential forward
selection" (SFS) (Bishop, 1997; Pudil et al., 2000; Somol &
Pudil, 2000) was developed to add the best (the one that leads to
the largest improvement in the value of the quality function) new
feature, at each successive stage of the algorithm, to the current
set of features until the needed number of features is reached. It
follows from construction that SFS suffers from the nesting problem
and always overlooks better solutions sets whose features are of
mediocre or poor quality. This is one of the shortcomings addressed
by the present invention. While "sequential floating forward
selection" (SFFS) also addresses the nesting problem, it maintains
exponential time complexity for large data sets. The second
shortcoming that this invention addresses is the exponential time
complexity to find "good" solutions. The proposed method and
invention finds a "good" solution set with high probability in
linear time with respect to number of predictors. One of the
floating search algorithms, called "oscillating search", (Somol
& Pudil, 2000) can also find approximate solutions in linear
time. However, the present invention and method guarantees an equal
or better quality solution while maintaining the linear time
complexity. In addition, the same generic method or algorithm can
be used not only for gene network reconstruction, but also can be
applied to protein data, feature selection for classification and
other biological data that is very large and complex to organize
and analyze.
SUMMARY OF THE INVENTION
[0008] The invention provides a method for determining a predictor
set of features associated with a target. The method comprises the
steps of selecting a predictor set of features, adding a complement
to the predictor set based on a quality of prediction, checking to
see if all of the features of the predictor set are repeated and
then removing one feature from the predictor set. The algorithm and
method repeats the steps of adding, checking and removing features
until the features of the predictor set are repeated. If the
features of the predictor set are repeated, the algorithm and
method terminate.
[0009] More specifically, the invention is a method for
probabilistically determining a subset of features of size k that
are closely related to a given target in terms of a selected
quality function. The method of the invention operates by allowing
a user to select a target of choice and the size (k) of the
predictor set. Once a target has been selected, the method starts
by selecting an arbitrary (ordered) subset of features of size k-1
and iteratively adds and removes single features (in order) from
the selected subset. This process is iterated until a subset of
features of size k is found whose quality of prediction of the
target can no longer be improved by the process of deletion
followed by addition of a feature. The algorithm terminates at this
stage. In each iteration, the comparisons are based on a quality
function that determines a quality of prediction associated between
the predictors and the target. The method of invention can easily
be extended to probabilistically determine the smallest (in size)
subset of features that are closely related to a given target
within an a priori set tolerance level in terms of a selected
quality function. The method then takes as input a given target
(user selected) and iteratively applies the method of invention for
subsets of size 1, 2, 3, . . . , k, etc., until a predictor set
that is closely related to the target expression, within the a
priori set threshold, is found. The method can also be used for
classification of experiments. The method in this case defines a
target in terms of a vector of numbers representing the class of
experiments under consideration. The method can then be used to
identify a subset of features which can classify the data.
[0010] The foregoing has outlined rather broadly the features and
technical advantages of the present invention in order that the
detailed description of the invention that follows may be better
understood. Additional features and advantages of the invention
will be described hereinafter which form the subject of the claims
of the invention. It should be appreciated by those skilled in the
art that the conception and specific embodiment disclosed may be
readily utilized as a basis for modifying or designing other
structures for carrying out the same purposes of the present
invention. It should also be realized by those skilled in the art
that such equivalent constructions do not depart from the spirit
and scope of the invention as set forth in the appended claims. The
novel features which are believed to be characteristic of the
invention, both as to its organization and method of operation,
together with further objects and advantages will be better
understood from the following description when considered in
connection with the accompanying figures. It is to be expressly
understood, however, that each of the figures is provided for the
purpose of illustration and description only and is not intended as
a definition of the limits of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] For a more complete understanding of the present invention,
reference is now made to the following descriptions taken in
conjunction with the accompanying drawing, in which:
[0012] FIG. 1 illustrates a schematic view of the present invention
in vector format showing the target and the predictors.
[0013] FIG. 2 shows a block diagram of the method of the
invention.
[0014] FIG. 3 shows how the GSSA algorithm makes comparisons of
data.
[0015] FIG. 4 shows a simulated plot of the number of attractors v.
the number of experiments.
[0016] FIG. 5 shows a simulated plot of the probability of finding
an optimal attractor v. number of genes.
[0017] FIG. 6 shows a simulated plot of the execution time v.
number of genes.
[0018] FIG. 7 shows a simulated plot of the execution time v.
number of predictors.
[0019] FIG. 8 shows a simulated plot of the log of the execution
time v. number of genes.
DETAILED DESCRIPTION
[0020] Before describing the present invention in detail, it is to
be understood that this invention is not limited to specific
compositions, process steps, or equipment, as such may vary. It is
also to be understood that the terminology used herein is for the
purpose of describing particular embodiments only, and is not
intended to be limiting. The invention has broad based use and
application in a variety of fields including most importantly the
fields of chemistry, biochemistry, computer science and
biology.
[0021] It must be noted that, as used in this specification and the
appended claims, the singular forms "a", "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "an attractor" includes more than
one attractor, reference to "a predictor" includes a plurality of
predictors and the like.
[0022] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0023] The term "feature" shall mean expression levels or
biological data of a defined gene, protein, or other biological
function or component under consideration and over a prescribed
number of experiments. It is also the smallest sized component or
item that can not be further reduced in a predictor set.
[0024] The term "network reconstruction" shall mean the process,
apparatus, steps and algorithms used in determining associated
and/or non-associated pathways in a data set. In particular, it
shall mean the relationships or pathways between two or more
predictor sets.
[0025] The term "target" shall have a broad based meaning to
include, proteins, genes, immunological information, feature
selection for classification, and other complex biological and
chemical data and or components that may be defined over a number
of experiments. The term has particular meaning to chemical and
biochemical data that is extensive, complex and difficult to
analyze. For instance, in the case of genes it shall mean the
expression levels over the number of experiments of a selected gene
of interest.
[0026] The term "predictor set" shall have a broad based meaning to
include, proteins, genes, immunological information, feature
selection for classification, and other complex biological and
chemical data and or components for a given size k, that are used
to compute or predict an associated quality or characteristic of a
target. For instance, in the case of gene vectors of a given size,
k, it is used to compute or predict an expression level of a target
gene vector.
[0027] The term "predictor(s)" is used for a feature that is part
of a predictor set.
[0028] The term "prediction" is a vector, computed by using a
linear/non-linear function of features in the predictor set
(although, we describe the proposed invention in terms of linear
prediction function, the method is not limited to the same; it can
be extended to other prediction functions such as non-linear,
etc.).
[0029] The term "quality" or "quality of prediction" shall herein
mean the distance between the predictor and the target. The smaller
the distance between the predictor and the target the better the
quality of prediction. Geometrically, for k=2, quality is the
distance between the target and the plane formed by the two
features in the predictor set. It should be noted that this
definition of the quality function should not be interpreted as
limiting and any other computable function may be used.
[0030] An "attractor" shall mean a set of a given size k of
features such that the quality can't be improved by replacing one
feature in the set. In other words, in the case of gene data, a set
of genes S is an attractor if the quality of its prediction of the
target gene, G, cannot be improved by substituting only one gene in
this set (in some sense an attractor is a local minima). It should
be noted that the best solution is always an attractor.
[0031] The term "complement" shall mean a feature (when looking for
a predictor set size of k features it is defined as follows: a
feature g is called a complement to a given set of k-1 features if
no other feature, along with this given set of k-1 features, can
form a higher quality set of k predictors). In the case k=2, gene
g* is called a complement to feature g if the "quality" Q(.,.) of
the couple (g,g*) is no worse than that of any couple (g,h);
Q(g,g*).ltoreq.Q(g,h) for any h.
[0032] The term "k-tuples" shall mean a group of size k. For
instance, if k=2, then we call them a "couple". In addition, if k=3
we call them a "triplet". This is an abbreviated term to show the
relationship between group size and designated pairings.
[0033] The term "good solution" shall mean a set of predictors
having a given size with high enough quality.
[0034] The term "M-dimensional space" shall mean a variety of
orientations and positions in space (i.e., M=1 . . . 1000,
arbitrary and large).
[0035] When a search for the best (in quality) group of individuals
is conducted, the term "nesting" or "nesting effect" shall mean
procedures that are based on the assumption that a good in quality
group consists of good in quality subgroups, overlooking solutions
made up of mediocre or poor (in quality) individuals.
[0036] The term "clustering" or "cluster" shall mean associations
made between previously non-associated groups or features. Clusters
are based upon potential pathway interactions rather than just upon
similar expression activity. Use of the method or technique in this
way can also allow the identification of genes, proteins or similar
type molecules, which are involved in predictor sets for many
targets, again leading to pathway identification.
[0037] The array is a significant new technology aimed at providing
a top down picture of the intimate processes of an organism.
Whether an array is implemented using photolithography and
silicon-based fabrication, capillary printing heads on a glass
slide, or ink-jet technology, it allows for quantification of large
amounts of data simultaneously. Few years have passed since the
first micro-array based biological results were published and it
already seems unthinkable to tackle the complexities of the
workings of the cell without these devices. However, there remains
unsolved image processing as well as computational and mathematical
difficulties associated with the extraction and validation of data
for micro-array assays.
[0038] Network reconstruction's main function is to discover the
existence and determine the association of multiple dependencies
between biological or transcriptional data that leads to the
identification of possible associated pathways. There are a number
of potential motivations for constructing algorithms, and computer
software for network reconstruction. For instance, diagnostics and
the diagnostic industry can use these techniques and tools for
application in disease identification. Other potential valuable
applications include treatment selection and outcome prediction. In
addition, the derived information can be further applied to aid in
drug development and areas of feature selection for
classification.
[0039] The references cited in this application are incorporated in
this application by reference. However, cited references are not
admitted to be prior art to this application.
Feature Selection in Pattern Recognition
[0040] The problem of network reconstruction, based on micro-array
data, can be reduced to finding dependencies within a subset of
features in terms of their expression levels. One meaningful option
to address this problem is to find a set of best k predictors for
any target of interest.
[0041] In the context of pattern recognition, machine learning,
data mining and their applications to various subject areas, e.g.,
medical diagnostics, manufacturing test design, image recognition,
etc., a similar problem of subset selection, known as feature
selection is faced. We have discussed this related work in feature
selection and the advantages of the proposed method over these
works in the Section "Background of the Invention". We concentrate
here on the method of invention.
[0042] The method described below is somewhat similar to what are
called the "sequential forward selection" (SFS) and "sequential
floating forward selection" (SFFS) methods. SFS adds the "best"
(i.e. the one that leads to the largest improvement in the value of
the quality function) new feature, at each successive stage of the
algorithm, to the current set of features until the needed number
of features is reached. In particular, SFS suffers from the nesting
problem and always overlooks better solution sets whose features
are of mediocre or poor quality. This is one of the shortcomings
addressed by this invention. While SFFS also addresses the nesting
problem, it maintains exponential time complexity for large data
sets. The second shortcoming that this invention addresses is the
exponential time complexity to find "good" solutions. The method
finds a "good" solution set in linear (with respect to k) time with
high probability. One of the floating search algorithms, called
"oscillating search", can also find an approximate solution in
linear time. However, the method guarantees an equal or better
quality solution while maintaining the linear time complexity. The
methods and algorithm of the present invention may be used and
employed in a variety of systems that receive or export large
volumes of data or information. In particular, the algorithm and/or
method have potential application with computer and/or computer
software. The algorithm may be used, employed or supplied with
other similar hardware, software, or systems that are well known in
the art.
[0043] Referring now to FIG. 1, the first step in a network
reconstruction entails the search for strong linear dependencies
among associated data, i.e.:
G.about.F(g, h . . . ) (1)
[0044] where G 120 is the target of interest and g 140, h 150 are
predictors. The function F can be linear or non-linear. In this
application, we investigate only the linear case:
F=.alpha.*g+.beta.*h (2)
[0045] where .alpha. and .beta. are constants.
[0046] The quality of a linear prediction of a target G 120,
associated with a set of features, g 140, h 150, is given by the
quality function Q 110: 1 Q ( G ; g , h ) = min a , b I = 1 m ( G i
- g i - h i ) 2 / I - 1 m G i 2 ( 3 )
[0047] FIG. 1 shows a representation of the g 140 and h 150 vectors
in 3 dimensional space. Each vector is defined by three components
x, y and z, which are the expression levels of a feature over a set
of three experiments. G, h and g are three arbitrary vectors in
3-dimensional space and the figure is for illustration purposes
only and should not be interpreted as limiting the scope of the
invention in any way. In addition, the use of x, y, and z
coordinate systems and the described planes should not in any way
be interpreted as limiting the broad scope of the invention. The
quality of a given pair g 140, h 150, as predictors of G 120, is
the distance between the plane formed by these two vectors and
target vector G 120 (See FIG. 1 for more details). G.sup.P 125 is
defined as the projection of G 120 on the plane 130 formed by g 140
and h 150.
Greedy Subset Search Algorithm (GSSA)
[0048] Referring now to FIGS. 1-3, the algorithm starts with an
ordered, randomly selected subset of k-1 features. Next, this
subset is complemented by one feature, which along with selected
features forms the best possible (in quality) subset of k features.
Number k is assigned to this feature. The feature number one is
removed from the set and numbering of remaining genes: 2, . . . , k
is reduced by one to become 1, . . . k-1. This subset of k-1
features is an input to the next iteration of the loop 315 (See
FIG. 3).
[0049] Iterations continue until the quality of a set of k
predictors can not be further improved by replacing any one feature
in the set 325 (See FIG. 3).
Method Outline: The Algorithm
[0050] Let S={g.sub.1 . . . , g.sub.n} be expression levels of N
features observed over the course of M experiments and let G 120 be
an arbitrary target with expression levels over the same group of
experiments. In this way, all features are represented by vectors
in M-dimensional space. G 120 may or may not belong to S 200 (not
shown in diagrams). In what follows, we will refer to every element
of S 200 as a feature.
[0051] General Definition
[0052] We say that a subset, s S 200, of features predicts the
target G 120, with accuracy 5 if the distance between the linear
subspace generated by s and G 120 equals .delta..
[0053] The Euclidean distance has been selected as a measure of
proximity. Given this, and the linearity of the subspace, the
definition above is simply stated as follows: the Least Squares
distance between the subset s and the target G 120 equals: 2 = min
; G g j S - j g j r; / ; G r; ( 4 )
[0054] where min is taken over all sets of k real numbers
.alpha..sub.j and .parallel. .parallel. represents the norm in
M-dimensional Euclidean space. The algorithm, in its current
implementation, doesn't take advantage of the specificity of the
distance definition and, therefore, can be applied to any search
problem of described nature with an arbitrary proximity measure.
The value of .delta. will be referred to as the quality Q(s) 110 of
a set of predictors s.
[0055] FIG. 2 shows a block diagram of the method of the present
invention and how the algorithm works with the predictor and target
data for a given size k of the predictor set. A target 120 of
interest is first selected (not shown in the block diagram, but
shown in FIG. 1). The method then selects an ordered subset of
features of size k-1. If k=2, then the method randomly selects a
feature, say g 140 (shown as reference number 200 in the block
diagram). To this subset the method now adds the complement
feature, i.e., to form the best subset of size k (in terms of
quality of prediction) that has the initially chosen subset of k-1
features. The quality of prediction of this subset of k features is
then noted (shown as reference 220 in the block diagram). Next, the
algorithm performs a checking step to see if the same set of k
features have appeared k times in a row (shown as reference number
225). If the answer is "yes" the algorithm stops and outputs the
set of k features as the result. This is called an attractor (shown
as reference numeral 230 in the diagram). If the answer is "no" the
algorithm removes in order one feature from the predictor set
(shown as 240 in the block diagram). The algorithm continues and
repeats the steps of adding a complement, checking the predictor
set and removing a feature until the same set of k features has
appeared k times in a row.
[0056] This process (of deleting a feature and adding another
feature) may be repeated many times until a subset is reached whose
quality of prediction can not be improved by deleting and then
adding a single feature. This subset of size k (k=2 here) is
referred to as an "attractor" 230 (shown generally as 230 is the
block diagram of FIG. 2). The method then terminates and outputs
the "attractor" as the best (in terms of quality of prediction of
the target expression) subset of size k (k=2 here). The process can
be modified, to probabilistically select the smallest (in size)
subset of predictors that is closely related to the target in terms
of the quality of prediction, as follows. The method starts with an
initial predictor set size of k=2 as described above. If the
"attractor" set that the method outputs does not lie within the
acceptable threshold of quality of prediction, the predictor set
size is incremented by one, i.e., k=3. The algorithm uses the
"attractor" of the previous stage (k=2) as the starting subset of
size k-1 at this stage. The method is iteratively applied with
increasing value of k, until an "attractor" is found that is
related to the target within the a priori set threshold of quality
of prediction.
[0057] Referring now to FIG. 3, the definition of "attractor" and
"complement" will now be clarified. FIG. 3 shows how a feature g
310 is first complemented by g* 320. g* 320 is a "complement" to g
310 implies that the set consisting of features g 310 and g* 320
has the best quality of prediction of all sets of size k=2 having
feature g 310. Feature g 310 is then removed and a new "complement"
feature g(.sup.2)* 330 is added to g* 320 and so on until the final
predictor set (g .sup.(k-1)*, g.sup.(k)*) 325 is found, such that
the "complement" of g.sup.(k)* is the same as g .sup.(k-1)*
(comparisons are shown by reference numeral 315). At this stage no
deletion or addition of a single feature can improve the quality of
prediction. Such a predictor set that can no longer be improved is
called an "attractor".
[0058] Definition of Complement(s):
[0059] Referring to FIG. 3, feature g* 320 is called a complement
to a set, i.e. g*=(s)* if the quality of the set s .orgate. g* is
better or equal to the quality of s .orgate. g for any choice of g
310, i.e.,
.orgate. g*).ltoreq.Q(s .orgate. g) (5)
[0060] Definition of Attractor(s):
[0061] A set of features s is called an attractor (with respect to
the complement) if (s')* .orgate. s'=s for any subset s' of s that
contains all but one element of s, i.e., one can not improve the
quality of a set of predictors s by substituting only one feature
(See FIG. 3).
[0062] The Problem and Algorithm:
[0063] For a given number k=2,3 . . . , a set of n features S, and
a target G 120, to find the best quality subset of features s of
size k. To solve the problem a random algorithm has been designed.
The main loop of this algorithm is defined as a cycle chosen for
one random seed set s'. For a given k, the solution starts with the
randomly selected seed set of genes s' of the size k-1.
1 One cycle of the main loop: Let s [i] represent the i.sup.th
element in s. Set index = 0; Randomly generate s' of size k-1; Set
current best attractor, s = .phi. (empty set); Repeat
unconditionally {
[0064] Find the complement g* of s', i.e., g*=(s')*;/* there is
always assumed seniority order in s, i.e., later complements have
greater index, e.g., g*=s[k]*/
2 If(s' .orgate. g* = s)then { s=s' .orgate. g*; index = index + 1;
if (index = k) then break out of the loop; } else /* find a new set
of better quality than s*/ { index = 1; s = s' .orgate. g*; } Form
new seed set s' as s without its first element s[1]; } Print set s
as the predictor set;
[0065] The number of cycles in the main loop can be controlled by
(i) the quality of a current set of predictors; (ii) total
computational time; and (iii) direct constraint on the number of
cycles itself. From a practical point of view, the above methods
are suitable for parallel processing. Since each loop begins with a
random subset of data, all that is necessary for the computation is
to allow the method to generate these random subsets, and compare
with previously computed best subsets. Therefore, different
initiations of the algorithm can be distributed across processors,
as long as different random seed subsets are used in each loop and
the computed best subsets are appropriately compared.
[0066] The algorithm above has been provided so that one of
ordinary skill in the art can design and write code from it. Java
software was used to code the algorithm in experimental runs.
Experiments and data were run on a Personal Computer (PC) with a
Windows NT (operating system). The system had 512 MB RAM and a 800
MHz CPU (processor). One of ordinary skill in the art needs to use
a programming language to make a software prototype of the
algorithm. He/she needs to have a computer that has the software
coding environment loaded. No special hardware requirements are
necessary to run this algorithm. The larger the size of RAM and the
more processing power (parallel processors would be even better),
the better. Methods in exhaustive searches are also well known in
the art and need not be described here in detail.
[0067] Algorithm performance:
[0068] It can be shown that one cycle of the main loop always
terminates and the predictor set it terminates at is an
"attractor". It is obvious that the best (in quality) set of genes
must be an "attractor" as well. Therefore, given everything equal,
the algorithm's performance depends on the number of "attractors";
the less the number of "attractors" the more likely the loop
terminates at the best "attractor".
[0069] If .pi. is the probability that one cycle of the main loop
terminates at the best "attractor", then the probability that after
P iterations of the main loop, the best "attractor" will be visited
at least once is:
1-(1-.pi.).sup.P (6)
[0070] It has been observed in numerous computations using both
generated and real data that as the number of "attractors" goes
down when the number of experiments (dimensions of space) goes
up.
[0071] In other words, as more independent experiments are
conducted, the reliability of the data improves. Since the number
of "attractors" reduces with increasing number of experiments, the
probability of finding the best in quality (optimal) "attractor",
using the GSSA algorithm, increases.
[0072] The probability, .pi., of finding the optimal "attractor",
however, goes down with the increase in the number of genes, N, and
the increase in the predictor set size, k. This is intuitive, since
the number of possible "attractors" will increase with an increase
in the number of genes or the size of the predictor set.
[0073] The figures described and illustrated below were plotted
using the software Matlab for PC. The PC was running Windows NT.
Other methods well know in the art can be used also to plot the
data. Matlab was used because of its simplicity in requiring (x and
y pairs) of data for plotting. These and other plotting methods are
well known in the art. However, the described applications and
plots should in no way be limiting of the broad scope of the
invention. The program can be coded to run on other computers and
different software may be used to plot the results. FIGS. 4-8 show
plots of data from a series of runs on the GSSA algorithm. The
plots show the application of the algorithm and method to gene
reconstruction.
[0074] FIG. 4 shows a plot of (Nattr) plotted against Nexp. The
plot shows the number of attractors of size 2 (i.e., k=2) as
dimensionality of the data increases. Each gene is represented as a
vector in m-dimensions. These m-dimensions are the m experiments
that were conducted on all the genes in the set S. This simulation
consists of expression of 200 genes in 40 experiments. Thus, size
of the set S is 200, and m=40. The graph shows how the number of
attractors of size 2 (k=2) decreases as more experimental values
are considered. It shows that as we use more experiments, we have
less number of attractors and hence, a better chance at reaching
the best solution in a few random runs of the GSSA algorithm. The
use of the algorithm provides a special blessing of dimensionality
toward a final solution. As has been described above, the number of
"attractors" can actually be controlled by the number of
experiments. In addition, the number of "attractors" can be
estimated a priori (proof beyond the scope of the invention).
Existence of multiple "attractors" for a given data set may be
evidence of insufficient amount of experiments to draw confident
conclusions regarding the nature of dependencies among genes. It
also suggests a specific number of additional experiments to be
performed to substantiate the conclusion.
[0075] Another point to be noted is that there is a tradeoff
between the number of genes replaced at each step of the algorithm
and the quality of "attractor". For instance, the computational
time increases exponentially as the number of replaced genes goes
up, but the algorithm may stop at a better quality "attractor".
However, one gene replacement algorithms converge to a high
"quality" attractor with high probability, given a sufficient
number of experiments.
[0076] FIG. 5 shows a simulated plot of the probability of finding
the optimal predictor set in a single run of the approximate
algorithm. As can be determined from the diagram, as the number of
genes increases the probability in most cases decreases in finding
the actual predictor set. FIG. 5. shows the probability to find the
best solution (best attractor of size k=numP in the graph) from a
set of N (x-axis of the graph) genes in one run of GSSA. One run of
GSSA means, starting with one random seed and running the GSSA
algorithm until an attractor is found. The dimensionality of the
data here (the number of experiments or m was fixed and was 38).
Three plots are shown in this figure. The top plot shows the
results for k=numP=2. The middle plot shows results for k=numP=3
and the bottom plot shows results for k=numP=4. The top plot and
other plots are similar. The top plot (k=numP=2) shows that the
probability of finding the best solution drops as we increase the
number of genes. This is because there exist more attractors as the
number of genes increases. Now the difference in the three plots
also shows that as we keep the number of genes fixed (take a fixed
value on the x-axis), but increase the value of k (i.e., increase k
from 2 to 4), we see that the probability of finding the best
solution also decreases (and this too is because the number of
attractors increases as the size of k increases). If .pi. is the
probability of reaching the best solution in one run of GSSA, then
the probability that it reaches the best solution in p trials is
1-(11-.pi.).sup.P which can be brought close to 1 if we increase
p.
[0077] FIG. 6 shows a simulated plot that demonstrates the
computational complexity of the approximate algorithm increases
linearly as opposed to an exponential increase using an exhaustive
search. The diagram shows a plot of execution time vs. number of
genes. It becomes evident that as the number of genes increases,
the execution time increases in a linear fashion. The fact that the
execution times (as the number of genes increases) lie on a line
indicates the linear nature of the algorithm. FIG. 6. shows the
execution time of running GSSA 50 times versus the total number of
genes. We take 50 random start seeds and run the GSSA until it
reaches an attractor for each of the 50 instances. Then we select
as the best answer, the best result of the 50. The size of set S of
genes from which to choose the predictors is increased in the
experiment. We see that the execution time increases linearly. The
three plots show for three cases (k=numP=2, 3,4). The exhaustive
search that finds the best solution has an exponential increase in
time.
[0078] FIG. 7 shows a simulated plot of the execution time of the
algorithm as a function of the number of predictors. The results of
the plot indicate that as the predictor set size increases, the
execution time also increases, but in a linear fashion. In other
words, the execution time does not increase at the same exponential
rate as exhaustive search when there is an increase in the number
of predictors. This is very important for calculations necessary in
the gene network reconstruction. What may take years to complete
(due to the exponential nature of exhaustive search) may now be
completed in a matter of few minutes. FIG. 7. keeps number of genes
fixed (S is fixed) and varies k=numP and plots the execution time
for 50 runs of the GSSA algorithm. The execution times can be
divided by 50 to yield time to run for a single run of GSSA (take
one random seed and run GSSA until you reach an attractor). Again
the execution time increases linearly with increase in k. Two plots
are shown for size of S=10, and 20. Note that the execution times
for FIG. 6. and FIG. 7. are for the algorithm implemented in Java
and running on a PC running Windows NT with a CPU of 800 MHZ and
256 MB RAM(memory).
[0079] FIG. 8 shows a plot of the log of execution time against
number of genes. The trend in this plot is similar to the trends
presented in the previous plots. The plot clearly shows the novelty
and power of the present algorithm in finding "good" solutions that
may be effective in the gene network reconstruction problem. FIG.
8. also shows the difference between execution times for the GSSA
algorithm and the exhaustive search. The number of genes (size of
S) is varied and the execution times are shown as log (to the base
e--natural logarithm). Here, we show time for only 1 run of GSSA
(as against 50 runs of the algorithm in FIGS. 6. and 7.). This
shows that this algorithm is extremely fast as compared to
exhaustive search methods that are well known in the art.
FURTHER APPLICATIONS OF THE INVENTION
[0080] The method of invention can easily be extended to
probabilistically determine the smallest (in size) subset of
features that are closely related to a given target within an a
priori set tolerance level in terms of a selected quality function.
The method then takes as input a given target (user selected) and
iteratively applies the method of invention for subsets of size
1,2, 3, . . . , k, etc., until a predictor set that is closely
related to the target expression, within the a priori set
threshold, is found.
[0081] The method of the invention can also be used for
classification. The method now defines a target in terms of a
vector of numbers representing the class of the experiments under
consideration. The method of invention can be used to identify a
subset of features that can predict the class of the experiment
within the given quality of prediction. As an example (though not
limiting the use of the invention), we can consider a micro-array
data for say, leukemia. The data consists of gene expression
results for different tissues (a tissue sample represents one
experiment) representing various types of leukemia. If we assign a
number for each type of leukemia (say, 0, 1, 2, etc.), then we can
define a target over all the experiments by the vector of numbers
representing the type of leukemia represented by the tissues. We
can now use the method of invention to identify a "good" subset of
genes that can predict the target vector (and hence the type of
tissues). Hence, these genes can form a diagnostic set of genes
whose expression values are used to discriminate between the
various types of leukemia.
[0082] Various modifications to the embodiments of the invention
described above are, of course, possible. Accordingly, the present
invention is not limited to the particular embodiments described in
detail above.
[0083] Although the present invention and its advantages have been
described in detail, it should be understood that various changes,
substitutions and alterations can be made herein without departing
from the spirit and scope of the invention as defined by the
appended claims. Moreover, the scope of the present application is
not intended to be limited to the particular embodiments of the
process, machine, manufacture, composition of matter, means,
methods and steps described in the specification. As one of
ordinary skill in the art will readily appreciate from the
disclosure of the present invention, processes, machines,
manufacture, compositions of matter, means, methods, or steps,
presently existing or later to be developed that perform
substantially the same function or achieve substantially the same
result as the corresponding embodiments described herein may be
utilized according to the present invention. Accordingly, the
appended claims are intended to include within their scope such
processes, machines, manufacture, compositions of matter, means,
methods, or steps.
* * * * *
References