Oncology Translational Laboratories:
Molecular Pathology Information
Management System
© Raj Bandaru 2010
View of Boston skyline from Novartis
Raj Bandaru, Sonia Agrawal, Humphrey Gardner MD.
OTL Statistics and Data management,
Novartis Institute for Biomedical Research.
San Diego, Pathology Visions 2010. Oct. 25.
Biomarkers of increasing significance
Novartis commitment to biomarkers in Treating patients
• Biomarkers in drug discovery and therapeutic paradigms: High priority
effort at Novartis.
• Numerous clinical trials underway focused on getting the best
treatments to the right patients.
• Deeply invested in measuring and understanding various biomarkers in
all our clinical studies (Pre, Phases 1 – 3 and post marketing).
• A highly data (biomarker) driven process that involves sampling and
collection of a large volume of data driving real time decisions.
•The Oncology Translational labs: center of excellence in Novartis to
ensure high quality and timely data delivery for making critical treatment
decisions
• Large part of this data is generated within our own labs to ensure high
quality and fidelity across studies.
2 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Customer: Oncology Translational Labs
Multi site / multi platform integration... In real time
•Tissue Biomarker Group (IHC),
•Molecular Pathology Lab, (CAP)
•Molecular Profiling Lab, (CAP/CLIA)
•DNA analyses/mutation detection
Cambridge, MA
East Hanover, NJ
•ELISA and proteomics
•Flowcytometry Lab
•Gene expression Profiling
Tissue Biomarker Group
(IHC)
Basel, Switzerland
6 pathologists, 12 Histotechs
.. Over 60 users across 3
sites
4 Aperio ® scanners
9 Ventanas ®, 2 Nemesis
2 CRI ® scanners/ imaging stations
2 3D Histech ® scanners,
Laser Microdissection
Circulating Tumor Cells, Veridex Celltrax ®
Sequenom ®, Fluidigm ®, Dxs, RTPCR,
Affymetrix ®, Nanostring® ABI ® sequencers...
Powerpath ® (validated database for CAP lab)
~ 15000 samples per year
(~ 70,000 slides)
Validated assays for > 30 analytes,
FISH, CISH, mutation/copy number
analyses = Millions of data points!
In hundreds of Spreadsheets,
emails, and other documents
3 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Life before the LIMS
Spreadsheets, emails... Perl scripts
• Samples and data recorded and tracked in Excel Spreadsheets.
• Laboratory processes not tracked or in systems not accessible (Ventana
system)
• Pseudo audit trails (periodic time stamped back up of all data files using
local scripts)
• Multiple data entry, sample tracking sheets, Ventana staining systems,
Aperio image database and Pathologist data entry.
• Data transfer and sharing via emailing of spreadsheets
• Data uploads to validated systems involved multiple independent and
repeated cross checks using non validated scripts.
4 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Tough Life
Errors, duplication of effort, redundancy and confusion
• Limited sharing/ security/audit trails/back up of the data
• Structure of folder / files not defined by the process in the labs
• Non transferable/ searchable data (color coding/ formatting of cells)
• No controlled vocabulary/ validation of data entries.
• Identified several errors and missing data (not entered or accidentally
deleted) in 2 years of legacy data. (from spreadsheets prior to 2006).
• Very difficult to implement automation, triggers, reminders.
© Raj Bandaru 2010
“Black clouds over San Diego Bay” taken with DroidX, Oct. 23rd AM
5 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Off the shelf solutions
Gaps
IHC... FISH... Copy number... RNA profiling.. DNA sequencing...
Range of Biomarker Assays
Primary limitation of off the shelf systems was the need for extensive
customization, expensive maintenance contracts/ consultation fees.
... And still require internal support teams.
Watson
LIMS
Molecular Profiling Assays
Histo Pathology Assays
Powerpath
Aperio
Spectrum
Ventana
LIMS
Increasing Automation/Digitization
6 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
What was missing
Phased implementation
step by step development with the big picture in mind.
Data
sources/
Labs
IHC
Aperio ®
STS
Enrollment
Log
OTL db
SMU
Clinical Statistics
data
export
RNA
Spotfire®
R toolbox
Flow
ELISA
Independent
database
Imaging
Misc. spreadsheets
External data
Preclinical/ cell line data etc.
7 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Reports
Analysis
Datamining
Key Requirements
What Information is tracked
• Log and track samples, child samples, arrays and sample meta data (subject
information, diagnosis), by studies/ projects, tissue microarrays.
• Create tasks/experiments, request tasks, log task metadata and process details.
• Two way communication link between Lab instruments and the LIMS.
• Store results/ data features associated with samples and compiled data sets and
associated analyses programs (SAS ® / R ® / Inform ®) and reports with e-signatures
• Link to external sample related data (images, pathology reports).
• Link to data mining/ analyses/visualization engines (Spotfire ®)
• Multilevel security, access restrictions at data and functionality level.
• Audit trail of edits, frequent back ups of data with recovery plans.
• Flexible and complex query interface to generate reports.
• Multisite synchronization of data, load distribution and performance opt.
• Automated emailing/ reminders / task tracking/ report generation.
• Customizable control vocabulary, data features, form display formatting.
8 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Interim Solutions
Preparing the labs for change
• Implemented automated backups and versioning of the spreadsheets and
data files.
• Updated spreadsheets automatically with data entered to the database.
• Partial integration with Aperio ® Spectrum via barcode scanning and
scripts to synchronize databases.
• Implemented Powerpath ® a validated database for the CAP/ CLIA
certification.
• Some limited customization of Spectrum ® and Powerpath ®.
• Set up scripts to extract data from Ventana ® run reports and load into the
LIMS.
•Started synchronizing sample identifiers across labs.
9 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
© Raj Bandaru 2010
Architecture
Validation focussed
• Windows server running Apache 2.0 Web server and PHP
• 64 bit Windows server running MSSQL 2005. (dev and prod instances)
• Plans to migrate production systems to validated servers (2011)
• Low level PHP/javascript/AJAX : highly structured code.
• Interface design, structure, actions, validation rules and function calls stored
within tables in database
• High on performance and ease of use, Low on bells and whistles.
• Highly modular, easily maintainable code. (Basic PHP developer friendly), Code
folders structure reflecting interface design, all SQL in one location/class.
Globals functions in specific classes
Database
Lookup form elements,
actions, form layout
specified in table
form
generator
form
processing
10 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
form
editing
Design
CFR21 Part 11
• Approximately 65 tables and ~
10 views plus audit trail.
• No records are ever deleted from
the database, just moved to
mirrored set of tables.
• Access restrictions by user/ user
groups at the level of tables,
fields in a table or specific data
elements.
• Very minimum server dependent
functionality to enable easy
porting to other database servers.
• Normalized database with
Optimized queries and compound
indexing.
11 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Interface
simple, clean and intuitive
12 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Interface
Simple and low learning curve
• Followed an Excel spreadsheet like feel, but via the web interface.
• Minimal user key strokes for data entry.
• Arrange tabs in order of workflow in the labs.
• Highly flexible query interface capable of complex searches with
unlimited filters and user defined reports.
• Ability to save searches and set up cron jobs to run searches/reports.
• User customizable web interface, formatting of fields, yet simple look
and feel.
13 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Timelines and Resources
Rapid development/ testing cycles
May 2007
May
Sept. 2008
May
Oct. 2009
April 2010
Jan. 2011
• On average one or two full time developers at any point. Indicated by
blue arrows above.
• Long term plan is to make code open source community include in a
public library for everything from LIMS to image and data analyses for the
Digital Pathology community
14 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Light at the end of the tunnel
Happy Pathologists and Histotechs
• Database contains over 120,000 records. (All legacy data ported
over).
• Modular code has allowed for rapid development of new functionality
(< 1 week from design to testing and production release)
• Far fewer errors or mistakes in the labs. Zero data errors.
• Some database performance issues to be resolved.
• Integration of other laboratory instruments and imaging stations.
© Raj Bandaru 2010
15 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
What is Ahead
Automation everywhere...
• Complete CFR21 part 11 Validation of the entire system.
• Reporting (Spotfire/business objects) and extend interface and
reporting on mobile devices
• Web access to analyses scripts and tools (SAS, R, Matlab code).
• Implement processing tasks creation logic interface.
• Wider acceptance of barcoding/ standardization of procedures.
• Text mining and knowledge management tools. Integrate with other
imaging and biomarker databases... MICAD, protein atlas, ncbi GEO,
Pubmed.
• General cosmetic/performance improvements. Google like searches.
© Raj Bandaru 2010
16 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
What is Ahead
Integration across technologies
Image Analyses with DNA analyses processes.
Track entire flow and process in the LIMS
Automated Tumor
finding algorithms.
(CRI ® inform)
Pathologist
verify
LCM and microdissect
tumor region
Histotech
supervise
Send for DNA
analyses
Analyses of Circulating Tumor cells and accessibility of images and results to Pathologists.
HSP 70
CK-PE
CD45APC
Processing of TMA core and Fluorescence images (CRI ® software)
Track and store application settings, data
outputs and resulting images. Make results
available via visualization tools.
17 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Thank you
Demo of development version
18 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Screen shots
OTL database
19 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Screen shots
OTL database
20 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Screen shots
OTL database
21 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only
Screen shots
OTL database
22 | Oncology Translational Labs IMS| Raj Bandaru | 20101024 | Informatics | Business Use Only