With increasing data volumes -- and issues specific to biological data findings -- the pharma industry needs to find new data mining and analysis techniques for the drug discovery process, including integrative analysis.
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Better Target Identification and Validation Through an Integrative Analysis of Biological Data
1. • Cognizant 20-20 Insights
Better Target Identification and
Validation Through an Integrative
Analysis of Biological Data
Executive Summary poses a peculiar challenge. In these fields, rela-
tionships among data sets are rarely simple and
Pharmaceutical target identification and valida-
often are not apparent without deeper investi-
tion today is an exercise in complex data mining.
gation. So geologists study aerial photography,
The amount, breadth and depth of biological data
satellite images, rock analysis and seismographic
available for such mining is increasing exponen-
data to attempt to locate oil basins; meteorolo-
tially, signaling both opportunities and challenges
gists examine ocean currents and surface tem-
for the biopharma industry.
peratures, barometric pressure, polar ice cover
More data should lead to more insights and better and more to predict climate conditions.
decisions. However, the sheer volume of available
The drug discovery process similarly requires
data is overwhelming. Further, biological data
assimilation and analysis of seemingly discon-
findings must be considered in the context in which
nected data sources with the goal of gaining
they were discovered and in light of their inter-
insights for forming a hypothesis to validate
actions and/or dependencies on other data sets
through experimentation.
and conditions. Integrating a wide variety of data
sets with such understanding of their contexts is In the initial steps of drug discovery, comprised
a major logistical hurdle for biologists. of target identification and validation, knowledge
of disease biology is crucial for picking the right
To fully capitalize on the rich biological data
targets. Arguably the biggest breakthrough
sources available today, scientists require a tech-
to that end was the completion of the human
nological platform that eases data integration and
genome sequence in 2000.
comparison across diverse types and sets of data
regardless of their sources. The complexity of the However, the genome sequence is static; it does
technology supporting this platform should be not reveal the dynamic role of the targets in a
hidden while it offers an easy, streamlined means variety of cellular circumstances. Today, this
of interpreting results. data is available through genomics technologies
like microarrays, which can be used to measure
Dynamic Context and Meaningful
thousands of mRNAs or DNA or proteins at
Biological Insights the same time. Now scientists have data at a
In predictive fields such as oil exploration, compu- molecular level along multiple cellular/molecular
tational finance, or climatology, data abundance dimensions that can help them understand the
cognizant 20-20 insights | august 2011
2. dynamic roles of targets in normal and diseased millions of data points with varied meanings.
biological processes. Each of these data types is distinct in terms
of its format, analysis and interpretation. For
The data volumes in public “omics”* data reposi- example, the normalization of CGH data needs
tories, like the Gene Expression Omnibus (GEO), to be handled very differently from that of
have grown exponentially in the decade since gene expression data.
the human genome was sequenced. A snapshot
of the type of data sets in GEO reveals that • Context as critical as data. The context of
omics data sets can be of varying types and that the experimental data is extremely important
microarray technology can be used to generate in the biological world. To generate quality
functionally diverse data sets. inferences and hypotheses, scientists need a
thorough understanding of how the experi-
Omics technological advances ments were performed. This context must be
Locked within like gene expression microar- preserved while integrating data for analysis.
these huge volumes rays and aCGH1 offering deeper
• Multiple public and proprietary data sources.
of data about a revelations about siRNAs2 and
A significant number of public repositories hold
miRNAs3 have enabled us to
cell’s DNA, RNA produce diverse and mammoth
valuable information about the experimental
findings of various facets of cell biology. In
and proteins and volumes of data. In fact millions
addition, every biopharma organization has
the relationships of data points can be produced
its own internal data sources and maintains
for a whole genome single run
among them are and aggregated to even larger
specific research findings. The types of data
and the sheer divergence of available data
the information and quantities in a very short time.
sources and the variations in data formats
insights required Concomitant with the explosion among these entities make it a formidable
to successfully of data is the need for spe- task for scientists to maneuver through the
data maze. Each of the data sources captured
identify and cialized data skills. Target
contains different levels of detail, so compari-
identification has become
validate high-value a data mining exercise. The sons can be challenging.
therapeutic targets. current challenge is how one • Lack of universally accepted standards.
can understand the dynamic The lack of common standards for data sets
context of the data, and analyze and interpret it results in the uncontrolled proliferation of data
to gain meaningful biological insights. It’s chal- as each research group describes the context
lenging for the lead biologist working on a target and the results of experiments in its own way.
to interpret and integrate the vast amount of Though standards such as Minimum Informa-
numeric data available in his decision-making tion About Microarray Experiments (MIAME)
process. This leads to underuse or improper use have been developed, multiple variants of
of high throughput data sets. MIAME have evolved to describe the complex
biological microarray experiments. These dis-
The Challenges of Mining Today’s parities mean scientists must manually look
Trove of Biological Data into multiple databases and correlate data
Locked within these huge volumes of data about among them to validate the observations — a
a cell’s DNA, RNA and proteins and the rela- time-consuming, tiresome task.
tionships among them are the information and
insights required to successfully identify and
• Need for complex visualizations. Visualiza-
tion plays a key role in finding the patterns in
validate high-value therapeutic targets. Yet the
the underlying data. The visualization tools
very nature of the data and how it is uncovered
for omics data have evolved from simple
create further challenges to using it effectively.
heatmaps to networks overlaying omics data
These challenges include:
and are continuing to evolve into three and
• Multiple data types from multiple high- four dimensions incorporating time series
throughput technologies. High-through- information. Researchers use various tools
put technologies have evolved to measure like Spotfire, R packages, Matlab, Excel and
different molecular entities in a cell, such as Cytoscape for visualizations. Typically, no
DNA, RNA, protein, methylation status, etc. single tool provides all the types of visualiza-
Each high-throughput experiment results in tions required by an omics researcher. Often,
cognizant 20-20 insights 2
3. researchers must develop custom visual- hypothesis generation even as it makes those
izations to address their specific research hypotheses more relevant.
questions.
We believe that an effective data integration
• Fast-evolving domain technologies. The solution enables productivity gains of at least
microarray technology that revolutionized 20%. Some of the key solution components that
biological data generation is now common, will drive such productivity gains are:
and several other high-throughput technolo-
gies, like next-generation sequencing, are • Faster insight generation.
evolving that further push the boundaries of The platform should inte- We believe that
data generation. As they do so, the challenge grate various public data an effective data
of effectively mining this data to establish sources and have the ability
useful biological insights becomes increasingly to combine those with com-
integration solution
critical to address. mercial and private data. It enables productivity
should help propagate bio- gains of at least 20%.
• Lack of a common platform. In many modern
pharmaceutical research organizations, logical insights using any
integrated access to all the data needed to of the common identifiers and be easy to use,
advance a discovery project is often impossible enabling scientists to more easily connect the
to achieve because it is spread across a variety data to reach insights.
of databases and visualization and analysis • More revelation of disease mechanisms.
tools. Thus, the scientists maintain their own Integrating different types of data should
personal copies of the data, typically in the help researchers investigate and understand
form of Excel spreadsheets, an inefficient disease mechanisms more thoroughly,
solution. which assists in building the target/disease
association.
• Annotated integration. Integration in the
usual sense is assimilating the parts into the • Maximize utilization of Oncology has long
whole. However, this traditional notion of inte- high throughput data
gration is not possible with biological data. It is sets. By providing easy
been a challenging
much harder to numerically integrate experi- access to diverse high- domain because of its
mental values in such a way that the resulting throughput data sets, complex biology. Our
number represents a biologically meaningful including those avail-
phenomenon. able within a company’s
goal with Inventus is
A more pragmatic approach is to integrate research groups and to help analyze the
the results from each experiment after systems, an integration data and answer key
platform would maximize
analyzing them separately. This approach
the return on invest-
questions around
can be extended to any molecular data type.
For example, tissue microarray data can be ment on generating such annotation for
analyzed independently by the pathologist, data sets. additional identifiers,
and the resulting inference of over-expression • Platform-independent gene ontology,
or under-expression of the protein of interest and extensible. The solu-
can be easily compared or integrated with the
mutation, expression
tion should be domain
over-expression or under-expression inference platform-independent and and pathway within
obtained from an RNA microarray experiment. be extended to open plat- the solution through
forms like caBIG or any
Making Information and Insights data propagation.
proprietary platform.
Obvious: An Integrated Solution
Researchers and scientists clearly need an intel- The Cognizant Approach: Inventus
ligent, intuitive solution to data collation and cor- We are creating a prototype for a biological data
relation so they can spend the majority of their integration platform using oncology as a thera-
time interpreting complex biological relationships peutic area. Oncology has long been a challeng-
and their impact on target identification and ing domain because of its complex biology. Our
validation. A single technology platform enabling goal with Inventus is to help analyze the data
a workflow that lets scientists look at different and answer key questions around annotation for
biological data types in context and to quickly additional identifiers, gene ontology, mutation,
analyze their relationships would streamline expression and pathway within the solution
cognizant 20-20 insights 3
4. Inventus Analysis Workflow
Validate by Wetlab
Experiments
Design & Conduct
Study Identify Gene
Pathway of Interest
Commons NCBI
Study Mutation
& Expression
COSMIC BioGPS
Figure 1
through data propagation. The typical analysis To demonstrate the utility of Inventus, we queried
workflow is depicted in Figure 1. for gene TP53, a well-studied tumor suppressor
gene. The default EntrezGene plug-in displays
As the next step, we investigated existing open the basic functional information about TP53. The
integration platforms like Life Science Grid (LSG) mutation plug-in displays mutation data for TP53
and cancer Biomedical Informatics Grid (caBIG). from COSMIC summarizing the mutations studied/
We built Inventus using LSG because it provided identified in various cancer types (see Figure 2).
the necessary minimal information technology The scientist is quickly able to understand that
framework. We developed the following plug-ins TP53 is frequently mutated in a wide variety of
for Inventus: cancers. The BioGPS plug-in displays the gene
expression data from the Novartis gene expression
• Web services-based pathway data from
atlas and shows TP53 to be under-expressed (see
Pathway Commons.
Figure 3). The above data quickly highlights to the
• Access to mutation data from
ept: Investigation of Gene TP53 COSMIC. scientist that TP53 could be involved in cancer.
• Web services-based gene annotation informa-
tion from NCBI EntrezGene. The pathway plug-in from Pathway Commons
tation
displays all the pathways that TP53 participates
ws the general known
• Portal-based data access to BioGPS.org for
(see Figure 4). One can observe that TP53 is
P53 like aliases, functional
gene expression.
involved in cell cycle pathways. Launching the
somal location etc
• Cytoscape for visualizing pathways. pathway in Cytoscape allows the scientist to
further understand the interacting partners
derstands that TP53 is a
Mutation Gene Expression
Proof of Concept: Investigation of Gene TP53
Step 3: Gene Expression
• Action
ws the mutations studied in • Scientist views the gene expression data
ata sources like COSMIC. from public data sources like Novartis Gene
Atlas.
tices that TP53 is frequently • Inference
cancer types. • Scientist notices that TP53 could be lowly
expressed in cancer tissues.
•
Step 4: Pathways
Figure 2 • Action Figure 3
s Confidential
• Scientist views the pathways that TP53 is
involved from public pathway data sources like
Pathway Commons.
cognizant 20-20 insights 4
• Inference
• Scientist notices that TP53 is involved in
various cell cycle pathways.