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=Brain Lesion Analysis in Neuropsychiatric Systemic Lupus Erythematosus=

==Objective==
This page describes the technology roadmap for lesion analysis in the NA-MIC Kit. Our objective is to create an end-to-end application allowing individual analysis of white matter lesions. This workflow applied to lupus patients is one of goals of the [[DBP2:MIND:Introduction|MIND DBP]].  The basic components necessary for this project are:
* '''Registration''': co-registration of T1-weighted, T2-weighted, and FLAIR images
* '''Tissue segmentation''': Should be multi-modality, correcting for intensity inhomogeneity and work on non-skull-stripped data.
* '''Lesion Localization''':  Each unique lesion should be detected and anatomical location summarized 
* '''Lesion Load Measurement''': Measure volume of each lesion, summarize lesion load by regions
* '''Time Series Analysis of white matter lesions''': Compare lesions between multiple scans taken over time.
* '''Multi-scale Analysis of white matter lesions''': Combine DTI, anatomical, and functional scans when analyzing lupus subjects.
* '''Tutorial''':  Documentation will be written for a tutorial and sample data sets will be provided

==Roadmap==
We obtained gray matter, white matter, CSF, and lesion maps for each subject based on T1-weighted, T2-weighted, and FLAIR images. Ultimately, the NA-MIC Kit will provide a workflow for individual and group analysis of lesions. It will be implemented as a set of Slicer3 modules that can be used interactively within the Slicer3 application as well as in batch on a computing cluster using [http://batchmake.org/ BatchMake].

The current status of the main modules to be used are:

=== Registration ===
:* Slicer has multiple image registration tools.

=== Lesion segmentation ===
:* A Slicer module has been created that implements a novel lesion segmentation method based on multi-level morphometric feature classification. (Scully)
Manual tracing will serve as a bronze-standard:
:* Slicer3 Manual tracing by clinically trained rater (Gasparovic/Bockholt)

=== Lesion Localization ===
:* Slicer3 has tools for labeling white matter lesions and summarizing their anatomical location

=== Lesion Load Measurement ===
:* Slicer3 has tools for measurement of labelled lesions

=== Performance characterization and validation ===
:* Data will be collected at both 1.5 and 3T. Data at 1.5T will be obtained with the protocol utilized for the current project on lupus at UNM.
:* Data at 3T will be obtained with sequences optimized for segmentation by the group at Utah.
:* Comparisons will be based on the approach developed by Martin-Fernandez et al.
:* The algorithm with the best performance will be incorporated into the NA-MIC kit.
 
=== Tutorial ===
:* 10 Externally sharable T1,T2,Flair,Lesion Map data-sets (NIFTI format) will be made available to the scientific community
:** 5 subjects with lupus and 5 healthy normal volunteers
:* A tutorial will be created that will guide end-users through each step needed to complete a lesion analysis in the NA-MIC kit
:** A step-by-step guide will be produced for one example lupus cases within the tutorial and one example healthy normal volunteer
:** Measurements for all 10 subjects will also be provided so that users may compare their results with those of the tutorial

=== Schedule ===
* Sequence Optimization and Data Collection
:* '''10/15/2007''' T1, T2, FLAIR optimized sequences for Siemens 3T Trio Tim scanner ('''Jeremy, Bruce, Chuck''')
:** We will work with Bruce Fischl on using MEMPR, Mugler, and FLAIR sequences that have been optimized for maximum constrast and minimal geometric distortion across sequences
:** '''DONE'''
:* '''3/31/2008''' collection of 5 lupus subjects on clinical sequence and optimized 3T sequence ('''Chuck''')
:** collected 2 patients and 3 controls so far
:*** as of 3/10/2008 there are 3-4 additional patients scheduled, since january 1, we have had 4 patients not able to complete the protocol so far

* Co-Registration and Atlas Registration
:* '''1/31/2008''' optimized mutual information registration for clinical sequences and optimized 3T sequences ('''Jeremy''')
:** we have tried the registration tools built-in to Slicer 3 EM-segment module so far
:** DONE Brad has implemented this successfully into the EM-segment module

* Lesion segmentation
:* '''3/17/2008''' complete lesion segmentation methods for Slicer3 EM-segment, ITK itkEMS, ITK lesion segmentation, and Slicer3 manual tracing ('''Jeremy, Chuck, Vince Magnotta, Kilian/Brad, Marcel''')
:** Slicer3 EM-segment Module
:*** (Resolved) Currently has a bug that does not permit 3 channel segmentation [http://na-mic.org/Mantis/view.php?id=205 Mantis ID#0000205]
:**** (Resolved) Only using 2 channels such as T1/T2 or T1/FLAIR does not produce sensible/usable results
:*** (Resolved) Does not properly allow user to edit or change weighting of channels, this is crucial for hierarchical lesion classification. [http://na-mic.org/Mantis/view.php?id=204 Mantis ID#0000204]
:*** EMSegment has been run against collected lupus cases.  Segmentations have improved but are still unusable as of 08/14/2008.
:**** Currently working with Killian on optimizing parameters in EMSegment to improve the lesion segmentation.
:**** Testing parameters and resulting segmentation on collected lupus cases. 
:** ITK itkEMS stand-alone package
:*** Marcel and Mark are in active collaboration with getting this method to work on-site, we have encountered compilation and memory problems with the package on mac and linux environments so far
:*** 3/17/2008 update, marcel built a 64-bit linux version that appears to run successfully, current results are are shown [[DBP2:MIND:itkEMSResults|here]]
:** ITK lesion classification stand-alone package
:*** Vince Magnotta has develop an ITK-based 2 stage lesion segmentation method
:**** stage one uses k-means tissue classification into grey, white, or csf of co-registered T1/T2
:**** stage two use bayesian classifier into normal tissue or lesion using results of stage one and co-reigstered Flair
:***** current results of this method as of 3/17/2008 are shown [[DBP2:MIND:itkBayesianLesion|here]]
:***** This method has been run against all cases as of 05/01/08.  Currently working with Vince Magnotta to improve the performance.
:***** As of 08/14/2008, currently running a modified version of Vince's classifier that has been improved by replacing intensity thresholding with joint histogram feature vector occurrence thresholding.
:** ITK K Nearest Neighbor Classifier
:*** Mark Scully is currently implementing a K-NN lesion classifier using ITK.
:**** This approach allows for on the fly additions to the classification model.
:**** The same segmentation approach is applicable to multiple lesion types.
:**** The resulting label map contains the percent likelihood that a given voxel is a lesion.  This allows the clinician to adjust the thresholding to match their preference.
:*** On hold as of 1/12/2008 due to incomplete ITK algorithmic support
:** ITK Custom Classifier
:*** Mark Scully is currently implementing a combined approach classifier using ITK.
:**** This approach allows for on the fly additions to the classification model.
:**** The same segmentation approach is applicable to multiple lesion types.
:**** This approach takes advantage of multiple approaches and advancements in the literature, including feature generation, Gentle Boosting based feature reduction, Artificial Immune System based filtering, and Bayesian classification.
:*** As of 1/01/2009 this method is functional and built into the lesion segmentation slicer3 applications. 
:***[[File:Scully_Figure1.png|Flowchart of lesion segmentation method]]
:***[[File:Scully_Figure4.png|ROC curve]]



:** Slicer3 Manual Tracing
:*** Gasparovic has manually traced all tutorial cases with lesions using T2/Flair images following tracing guidelines and a qualitative neuroradiological review report
:**** 4/1/2008 create manual tracing guidelines documentation and share here
* Lesion Localization
:* '''4/15/2008''' complete lesion localizations and maps for Slicer3 EM-segment, ITK itkEMS, ITK lesion segmentation, and Slicer3 manual tracing ('''Jeremy, Chuck, Vince Magnotta, Steve''')

* Lesion Measurement
:* '''4/20/2008''' complete lesion measurements and regional lesion load summaries for Slicer3 EM-segment, ITK itkEMS, ITK lesion segmentation, and Slicer3 manual tracing ('''Jeremy, Chuck, Vince Magnotta, Steve''')

* Performance characterization and validation
:* '''1/6/2008''' [[Media:DBP2_MIND_Lupus_200801_update.ppt | report]] to 2008 NA-MIC AHM on progress for performance and validation of lesion segmentation methods for EM-segment, BRAINS2, manual, UNC packages ('''Jeremy''')
:** '''DONE'''
:* '''5/15/2008''' submit abstract on reliability and summary of novel NA-MIC kit lesion analysis method ('''Jeremy, Chuck, Mark Scully, Brad, Kilian, others''')
:** plan is to submit SFN abstract and manuscript closely after
:* '''5/20/2008''' analyze NIH study clinical sample using NA-MIC kit lesion analysis method ('''Jeremy, Chuck, Mark Scully''')
:* '''7/1/2008''' submit manuscript on clinical application of NA-MIC kit lesion analysis method ('''Jeremy, Chuck, Mark Scully, Carlos Roldan, Bill Sibbitt''')
:* '''8/14/2008''' submit manuscript on the lesion segmentation methods as applied to MS lesions for MICCAI 2008. ('''Mark, Jeremy, Chuck, Vince Magnotta''')
:* '''1/11/2009''' submit abstract on the new lesion segmentation methods as applied to Lupus lesions for HBM 2009.
:* '''3/08/2009''' submit manuscript on the new lesion segmentation methods as applied to Lupus lesions for MICCAI 2009.

* Incorporation of approach into NA-MIC kit
:* '''1/6/2008''' Slicer3 Lesion Analysis Module that handles co-registration of T1, T2, and Flair ('''Mark Scully, Steve''')
:** DONE Brad completed this 
:* ''5/1/2008''' extend Slicer3 Lesion Analysis Module to handle lesion localization and measurement ('''Mark Scully, Steve''')
:** ''08/01/2008'' currently locates all independent lesion clusters and identifies the anatomical regions, provided by a registered atlas, that the lesions overlap.
:* '''6/1/2008''' extend Slicer3 Lesion Analysis Module to implement the ITK-based lesion analysis algorithm/method (EM-segment, ITK itkEMS, ITK lesion segmentation) with the best performance ('''Mark Scully, Steve''')
:** a demonstration will be given at the 2008 NA-MIC AHM--we would consider this version a prototype and would be testing, refining the module through the clinical application phase ('''Jeremy, Mark Scully''')
:* '''6/15/2008''' functioning prototype version of lesion analysis Slicer3 Module complete ('''Mark Scully, Steve''')
:* '''8/14/2008''' in the process of creating a module that "chains" together all of the steps in the lesion segmentation analysis pipeline.
:* '''1/03/2009''' Newly developed lesion segmentation method with significantly increased performance incorporated into Slicer3 module.
* Tutorial and Data-sharing
:* '''6/20/2008''' present tutorial to 2008 NA-MIC programming week ('''Mark Scully, Jeremy, Sonja''')
:** A logical project for programming week for Jeremy and Sonja to finish public version of tutorial
:* '''7/1/2008''' make data sets and tutorial available to the scientific community ('''Mark Scully, Jeremy, Sonja''')
:** If we submit SFN abstract, we can advertise the availability during SFN Conference in November 2008
:*** We could think about advertising the roadmaps at the BIRN booth at SFN this year?
:* '''10/15/2008''' In the process of making the tutorial data available using XNAT.



Compare view of baseline and followup with color-coded lesion differences:
http://www.na-mic.org/Wiki/index.php/File:CompareViewFlairLesionDiffWholeBrain.png

Diffusion tracts intersecting a lesion volume:
http://www.na-mic.org/Wiki/index.php/File:LesionTractsNear.png

Axial slice with % predicted chance, thresholded predicted % chance, and manual tracing:
http://www.na-mic.org/Wiki/index.php/File:Scully_Figure3.jpg

=== Team and Institute ===
* Co-PI: [http://www.mrn.org/principal-investigators/h-jeremy-bockholt H Jeremy Bockholt]  (jbockholt at mrn.org)
* Co-PI: [http://www.mrn.org/principal-investigators/charles-gasparovic-ph-d Charles Gasparovic] (chuck at unm.edu)
* Software Engineer: Mark Scully (mscully at mrn.org)
* NA-MIC Engineering Contact: [http://www.na-mic.org/Wiki/index.php/User:Pieper Steve Pieper], Isomics
* NA-MIC Algorithms Contact: Ross Whitaker, Utah
* Host Institues: The [http://www.mrn.org Mind Research Network] and [http://www.unm.edu The University of New Mexico]

[[Category:Slicer]] [[Category:Segmentation]] [[Category:Registration]]