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ABSTRACT
J Pathol Inform 2011,  2:43

Abstracts: Pathology Informatics 2011 Meeting


Date of Web Publication03-Oct-2011

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How to cite this article:
. Abstracts: Pathology Informatics 2011 Meeting. J Pathol Inform 2011;2:43

How to cite this URL:
. Abstracts: Pathology Informatics 2011 Meeting. J Pathol Inform [serial online] 2011 [cited 2017 Apr 23];2:43. Available from: http://www.jpathinformatics.org/text.asp?2011/2/1/43/85679


   Scientific Session Top


Session-1

Imaging

Wednesday, October 5, 2011 (7:30 am - 8:55 am)


Grand Ballroom 1

An Entirely Automatic Method to Score Crypt Loss and Infiltration from Pathology Slides in a Mouse DSS Model of Colitis

Cleopatra Kozlowski, Jason deVoss, Joseph Beyer, Lauri Diehl

Genentech, South San Francisco, CA.

E-mail: cleopatk@gene.com

Content

The DSS (dextran sodium sulfate) model of colitis is a mouse model of inflammatory bowel disease, a condition that affects more than 1 million people in the US alone. Microscopic symptoms include loss of crypt cells from the gut lining, and infiltration of inflammatory cells into the colon. An experienced pathologist requires over 6h for 100 H&E slides to manually score loss of crypts in selected regions of the mouse gut. In order to increase the efficiency of scoring, we devised an entirely automatic method to quantify loss of crypt cells in the whole slide.

Technology

We used Definiens Developer (Definiens AG, Munich, Germany) to design an image analysis algorithm.

Design

The method relies on a combination of morphological and intensity based features of every tissue area, as well as a neighbor-based classification method. Further, we developed another entirely automatic method to count infiltrating macrophages, neutrophils, and T cells in IHC of serial sections to the H&E slides.

Results

We found an overall correlation of > 0.7 between independently assigned automatic and manual scores, in approximately 800 DSS treated mice. The correlations were robust across 12 studies, in spite of large variations in slide quality and staining intensity. Though the analysis requires approximately 40min of CPU time per slide, cluster computing allows us to analyze up to 500 slides overnight without any manual intervention.

Conclusion

Overall, our methods greatly facilitate the scoring of mouse colon in DSS induced colitis, and enable quantitative analysis of morphological tissue changes and cell infiltration.

A New Method for Analyzing Cellular Protein Patterns from Routine Histopathology Images

Gustavo K. Rohde, Wei Wang, Cheng Chen, Dejan Slepcev, John A. Ozolek

Carnegie Mellon University, Department: Biomedical Engineering, Pittsburgh, PA.

E-mail: gustavo.rohde@gmail.com

Content

We describe a new technology for analyzing the morphology of cells and subcellular structures from digital pathology image data. The new approach is substantially different from existing technology in that it allows for visualization and discovery of meaningful differences in subcellular protein patterns in normal vs. cancerous cells.

Technology

Following automated image segmentation, the differences between normal and cancerous cellular patterns are computed by transporting (morphing) one pattern into another. The morphing operation allows for the definition of a distance as well as a path from one structure to another (Figure 1), to which all other structures can be compared. The differences between two sets of patterns can be found by computing the path that best separates them according to the standard p value. In contrast to standard numerical feature-based approaches, the method we describe allows for easy and meaningful visualization.



Design

We apply our methods to decoding differences between protein patterns (nuclear chromatin, as well as golgi protein patterns) in normal and cancerous cells. Groups of cells are then compared to elucidate the differences in structure that are present in the data. Nuclear chromatin patterns imaged using Feulgen staining from 10 thyroid cases (normal thyroid, follicular adenoma, follicular carcinoma), 5 liver cases (normal, fetal-type hepatoblastoma) and two proteins (giantin and gpp130) in the golgi apparatus of HeLa cells imaged with immunofluorescence. Patterns are first normalized for translation, rotation, as well as size (optional).

Results

Results show that nuclear chromatin patterns in normal liver vs. hepatoblastoma differ, and that the most significant difference (in the sense of p value) is that normal cells tend to have chromatin more densely packed while cancerous cells tend to have a more disperse distribution (Figure 1). Results describing differences between normal thyroid, follicular adenoma and carcinoma, as well as two golgi protein patterns in HeLa cells, will be shown.

Conclusions

The spatial distribution of cellular patterns can contain important biological and diagnostic information. The new method described is able to process the image data automatically with the end of facilitating visualization of important differences between normal vs. cancerous cells.

Experience with Cellvision TM DM96 for Peripheral Blood Differentials in a University Hematology/Oncology Center

M. Rollins-Raval, Lydia Contis

University of Pittsburgh Medical Center Division of Hematopathology, Pittsburgh, PA.

E-mail: rollinsravalma@upmc.edu

Content

Rapid, accurate peripheral blood differentials are essential to maintain standards of patient care. CellaVision TM DM96 (CellaVision AB, Lund, Sweden) (CV) is an automated digital morphology and informatics system used to locate, pre-classify, store and transmit platelet, red and white blood cell images to a trained technologist who confirms or edits CV cell classification. Efficiency of CV increases as the need to edit classification (i.e. technologist time) decreases. We assessed our experience with CV by evaluating both percentage of correct pre-classified cells out of CV initial classification (CPC/CVI) and percentage of correct pre-classified cells out of total number of verified cells for different cell classes (CPC/VC) in a university hospital with a large hematology/oncology patient population.

Technology

CellaVision TM DM96 (see Content).

Methods

Using CV's Database Query Tool, Version 4.2 (CellaVision AB, Lund, Sweden), we analyzed classification accuracy of CV for white blood cells, erythroblasts, platelets and artefacts over six months.

Results

The CV classified 211218 events. For all events, CPC/CVI and CPC/VC reached 94% and 93%, respectively. Values for segmented neutrophils, eosinophils, lymphocytes, monocytes, giant platelets, smudge cells and artefacts were > 80% for both CPC/CVI and CPC/VC. CPC/CVI and CPC/VC were < 80% for immature granulocytes (band neutrophil, promyelocyte, myelocyte and metamyelocytes) (differences usually within one stage of maturation) (Table 1).



Conclusions

Reduced immature granulocyte classification accuracy may be due in part to the subjectivity in classification of these cells, length of experience with the system and individual expertise of the technologist. Cells with low CPC/CVI and CPC/VC comprised a minority of the cells and should not significantly affect the technologist re-classification time. CV serves as a clinically useful instrument in performance of peripheral blood differentials.

An Accuracy Validation Framework for Automated Pathology Image Segmentation and Classification Algorithms

Jingjing Gao, Jun Kong, Fusheng Wang, Tahsin Kurc, Lance Waller 1 , Joel Saltz

Emory University, Center for Comprehensive Informatics and 1 Department of Biostatistics and Bioinformatics, Atlanta, GA.

E-mail: jgao@emory.edu

Content

A major challenge in digital pathology is the large inter-observer variability among pathologists. As pathology has largely been a qualitative discipline, significant disconcordance in human diagnosis is well observed. Consequently, computer-based methods have been developed to execute such tasks as nuclei segmentation and classification. Due to the large number of nuclei in pathology slides, the algorithm accuracy and precision validation are often lack of statistically theoretical support. In practice, researchers usually make visual assessments by overlaying the results on raw images. To address this problem, we designed a generic human-guided validation workflow both statistically defensible and reproducible.

Technology

To minimize the validation efforts required from human experts, statistical stratified sampling technique was adopted to select sub-regions from whole-slide pathology images. Sub-region images were clustered into strata by K-means analysis on imaging features. Sample size was calculated based on preliminary analysis. For human annotations, original images were pre-loaded to the Aperio image server to facilitate nuclei annotations by pathologists. Human markups were then transferred into a pre-setup Pathology Analytical Imaging Standards (PAIS) database with built-in query functions for spatial based measurements. Numerous distance- and region-based measurements along with the statistical agreement test were performed at sub-image and whole-slide level, making the algorithm validation process definitive.

Design

We design the workflow as follows. First, a set of sub-images with pre-determined sizes were randomly selected from strata identified by the clustering analysis based on imaging features. Secondly, we applied a variety of algorithms to selected sub-images for nuclei segmentation and classification. Human expert markups were also captured through an image viewer (Aperio ImageScope Client), transformed into PAIS document format and then loaded into PAIS database. Finally, computer generated segmentations were compared to human annotations using distance-based, region-based metrics and statistical agreement indices.

Results

To assure the scalability and generalizability of the proposed framework, four types of brain tumors, namely, glioblastoma, oligodendroglioma, oligoastrocytoma and astrocytomas with various grades, were included in the scope of tests. Four sub-regions were randomly selected from clusters stratified on imaging features for each slide. A total of 431 nuclei were segmented by a computationally efficient algorithm and an experienced neuropathologist. With the theory of survey sampling and the measures from stratified randomly sampled sub-regions, we estimated the means of three measures (overlapping-ratio, centroid-distance, and Hausdorff-distance) for each slide and provided a 95% confidence interval for each estimated mean. Our tests suggest that 95% of the time the mean of overlapping ratio for a selected slide is within the range (0.791, 0.802). This implies concordance between human and algorithm on nuclei segmentation.

Conclusions

We have proposed a design pattern for a representative use case from the biomedical and clinical research domain that aims at validating segmentation and classification algorithms for pathology images.

Design and Evaluation of a Virtual Reality Microscope

Darren Treanor, Rebecca Randell, Rhys Thomas, Roy Ruddle

University of Leeds, Pathology and Tumour Biology, Leeds, United Kingdom.

E-mail: darrentreanor@nhs.net

Content

We have been developing a virtual reality (VR) microscope that could be used for viewing digital slides for diagnostic work. Using existing systems, it can take up to 60% longer to perform diagnoses using digital slides than on the light microscope. Our goal is to develop a VR microscope that allows diagnoses to be made quicker, but as accurately as, a conventional microscope, an essential step in making digital pathology suitable for routine use. We are achieving this by combining ultra-high resolution displays with VR technology and 'intelligent navigation' techniques.

Methods

An iterative approach to development and evaluation is being taken. A first version of our VR microscope went through a phase of formative evaluation and the feedback from this was used to refine the software. We then evaluated the VR microscope using a mixed factorial experimental design with technology (2 levels, conventional microscope and VR microscope) and task (2 levels) as within-participant variables and grade of pathologist (2 levels) as a between-participant variable. We had 16 participants in the evaluation.

Results

No significant difference in time taken to come to a diagnosis was found between the conventional microscope and VR microscope. We will also present findings regarding diagnostic confidence, diagnostic accuracy, pathologist preference, and navigation patterns in the two conditions.

Evaluation of Different Display Modalities for Whole Slide Images in Pathology

Gaurav Sharma, Gautam Sharma, Abid Shah, Anil Parwani, Walid E. Khalbuss, Sara E. Monaco, Alka Palekar, Rajendra Singh, Liron Pantanowitz

University of Pittsburgh Medical Center, Division of Pathology Informatics, Department of Pathology, Pittsburgh, PA.

E-mail: sharmag@med.umich.edu

Content

Diagnostic accuracy and user confidence at interpreting whole slide images (WSI) of digitized surgical pathology (SP) and cytopathology (CP) slides depends in part on the presentation and perception of WSI. The aim of this study was to compare the user experience with different display (computer monitor) modalities.

Technology

Laptop monitor - IBM Thinkpad 14.1 inch (LPTP), non-medical grade monitor - HP ZR24w 24 inch (NMGM), medical grade monitor (small) - Eizo FlexScan SX2462W 24 inch (MGM1), medical grade monitor (large) - Barco Coronis Fusion 6MP 30 inch (MGM2), optical microscope - Leica DM2000 (OM), WSI scanner (Aperio Scanscope XT), WSI browser (Aperio Imagescope 10.2), data storage - portable hard drive (Seagate Free Agent 1 TB).

Design

Glass slides from 60 cases (30 SP, 30 CP) of varying difficulty were digitized. WSI stored on a portable hard drive were randomly reviewed on 4 different monitors under standard conditions and also examined with an OM by 6 pathologists with a washout period of 2 weeks. Each pathologist reviewed 30 slides based on their area of expertise. Data was captured on a graded scale (high, medium and low) for 8 parameters (see table).

Results

Results from 900 encounters (720 electronic and 180 OM over 3 months) are shown in the table.



Across SP and CP, the difference in image quality and diagnostic confidence was statistically significant (P<0.001) between medical grade modalities (MGM1,2 and OM) compared to non-medical grade modalities (LPTP and NMGM). Monitor brightness was the most frequent (13.19%) screen adjustment.

Conclusions

Non-medical grade displays had inferior user experience compared to medical grade monitors and the light microscope. Although comparable to the microscope, limiting issues with MGM include pixilation and prolonged refresh lag. With advances in display technology, MGM would be the optimum modality to electronically display WSI.

Session-2

Hospital / Lab OPS

Wednesday, October 5, 2011 (7:30 am - 8:55 am)


Kings Garden North

Duplicate Patients: Considering Clinical Priority in Resolving Patient Registration Errors

Peter Gershkovich, John Sinard

Yale Medical School, Department of Pathology Yale University School of Medicine, New Haven CT.

E-mail: peter.gershkovich@yale.edu

Content

Over the past ten years the number of duplicate patient records in our anatomic pathology laboratory information system (AP-LIS) has significantly increased. The increase is caused by electronic integration between multiple Hospitals and Clinics in the absence of a Unique/Universal Patient Identifier. We discovered that the existing built in mechanism for identifying potential duplicate patients does not take into account clinical timeline and priorities. In addition it is inadequate in discovering all duplicates. Finally, processing duplicate patients is time consuming and needs to be done by skilled staff members. As a result, last year in up to 70 percent of merged patients in a given month, pathologists were not aware of prior material at the time of making a diagnosis.

Technology

The new software to identify duplicates is written in Java and is encapsulated as a "Job" in RTSE, an acronym for Repetitive Task Scheduling Engine, developed in-house. RTSE uses a Quartz framework for scheduling and running jobs; it is integrated into the operation of our CoPathPlus (Cerner DHT, Waltham MA) information system through a direct access to the underlying database.

Design

The encapsulated "Job" is activated based on a configurable schedule. It selects active cases from CoPath and passes them to an algorithm with an intuitive scoring system for evaluating potential duplicate patients. Selected patients are listed with corresponding demographic information, case priority, number of prior specimens associated with the potential duplicate, and the time since working draft for the case has been printed. The Duplicate Patient Report is sent to appropriate staff via email. In addition, a flag has been established within CoPath to alert the pathologist at the time of signout if the patient has been recently merged or has a potential merge pending processing.

Results

Resolving duplicates is now done in the context of clinical priorities, increasing the likelihood that pathologists will know about prior material before finalizing the diagnosis or ordering additional tests. The improved algorithm allows better control over sensitivity and specificity for the selection of potential duplicates.

Conclusions

More duplicate cases are resolved prior to rendering of the Pathological Diagnosis, providing better continuity of care and reducing the number of unnecessary tests.

An Automated System for Managing the Storage and Retrieval of Organisms Isolated in the Microbiology Laboratory

Richard Hill, Kavous Roumina, Walter H. Henricks

Cleveland Clinic, Center for Pathology Informatics, Cleveland, OH.

E-mail: hillr4@ccf.org

Content

A microbiology isolate is an organism that is "isolated" from culture of a clinical specimen. Microbiology laboratories have a need to identify and archive isolates that represent organisms that may require additional antimicrobial testing, are unusual, are from critical sites, or are used in validation of new equipment and assays. The Micro Isolate Storage (MIS) system was developed to replace manual, error-prone, time-consuming manual data maintenance for stored microbiology isolates.

Technology

Application in Visual Basic 6.0 (Microsoft); relational database (Access 2003, Microsoft); laboratory information system (Sunquest).

Design

In the laboratory information system, laboratory technicians enter isolate data including organism name, result codes, and patient demographics, and also set a "flag" that the isolate is to be archived. Data elements from flagged specimens are extracted daily from the laboratory information system. The system imports extracted isolate data into a database, and presents data to users to review for completeness and accuracy. The system then automatically assigns storage (box) locations and generates a report containing the isolate type, accession number, specimen identification number and storage location, in the exact sequence to be archived. The system allows for specification of storage box types and sizes, and tracks isolates removed from or returned to storage. The system can retrieve data based on patient demographics, organism type, date range, and/or specimen identification number.

Results

Over 16 months, 9,859 isolates have been processed, averaging 616/month. An efficient electronic procedure replaced unnecessary manual work and logs, increasing data accuracy and saving 4-8 hours/month labor in managing isolates. The system also enables quick retrieval of isolates, saving an additional 2-4 hours/month.

Conclusion

The Micro Isolate Storage system has improved the efficiency and reliability of managing microbiology isolates. Manual archiving processes have been eliminated, and the accurate retrieval of isolate-related data and status using a variety of search criteria is now possible.

Implementation and User Satisfaction with LIS in Forensic Pathology

Bruce P. Levy

Massachusetts General Hospital, Department of Pathology, Boston, MA.

E-mail: bplevy@partners.org

Content

Medical examiner offices have unique requirements for the collection, preservation and reporting of data and conclusions related to death investigations. Forensic pathology laboratory information systems need to appropriately address these issues. The market for these systems appears to remains immature, with the few available commercial products being adaptations of home-grown, in-house products.

Technology

The significant commercially available products include CME-VertiQ, Justice Trax, Quincy and BEAST. In-house systems have been created using mostly utilizing Microsoft Access or Microsoft Excel.

Design

A survey of medical examiner offices was conducted in 2007 to evaluate their usage of forensic pathology laboratory information systems. Information regarding the systems that were in use and the user's opinions of the systems were obtained and analyzed. The same survey is being conducted in 2011 with the goal of observing changes and trends in the market.

Results

In 2007, a total of 78 medical examiner offices in 36 states responded to the survey. Among the responding offices, 22% did not have a forensic pathology laboratory information system, 33% were using systems developed in house and 46% were using a commercially available product. Only half of the responders would recommend their system to another office, with 46% of in-house and 57% of vendor purchased offices making such a recommendation. Only 63% of systems had some access to images. The 2011 survey is currently being conducted. The 2011 results will be evaluated, compared to 2007 survey results and presented at the conference.

Conclusions

Preliminary results indicate that the market for forensic pathology laboratory information systems appears to remain immature. Most commercially available systems continue to be represented by adaptations of in-house systems, and many offices continue to use and develop their own systems. The small size of this market will continue to keep major developers uninterested and restrict development of more advanced systems despite user's interest in improved systems.

Development and Deployment of Pathologist-Driven Electronic Billing Module: Overcoming a Dysfunctional Workflow

Philip J. Boyer, Mark L. Gallen, Adam L Kanallakan, Heidi M. Gullord Wendt, Kathleen Zeleski, Miriam D. Post

University of Colorado Denver, Department of Pathology and University Physicians, Inc., Aurora, CO.

E-mail: philip.boyer@ucdenver.edu

Content

The anatomic pathology billing process at the University of Colorado Hospital (UCH) had been entirely paper-based with an inefficient workflow that lead to delays of over 38 days on average from "date of service" (DOS) to the initial "date of posting" (DOP) into the UCH physician practice billing division (University Physicians Incorporated, UPI) billing system. Originally, departmental billing experts did all coding manually on paper, with paperwork returned to the sign-out pathologist for review and manual signature, with transfer of finalized paperwork to UPI for data entry. We sought to design an electronic billing (E-billing) system that would stream-line the billing workflow.

Technology

Billing fields were established in a Microsoft (MS) SQL 2008 database used by Cortex, the UCD anatomic pathology laboratory information system. A client-server billing module was developed using MS VB.net, with separate pathologist and biller clients. The module is opened when a pathologist signs out a case based on a call using MS VBScript from within an MS Word. dot document. Pathologists access a "denial" queue within the module by a desktop icon where billing changes recommended by billers are accepted or rejected.

Design

The original and post-E-billing implementation workflows for surgical pathology cases were compared with respect to the number of steps, reasons for delays, staffing needs, and time-course using LEAN process improvement methodology. Primary goals included (1) reduction in the DOS to DOP interval for one pathologist (MP) involved with the billing process, (2) implementation of coding by pathologists, with review by billers, (3) meeting of Centers for Medicare and Medicaid Services (CMS) guidelines, (4) electronic transfer of data to UPI, and (5) elimination of paper- and manual-based processes.

Results

Implementation of an advanced version of the physician-driven e-billing system reduced the DOS - DOP interval by an average of 16 calender days (from 37.3 to 21.8 days) with electronic sign-off that meets CMS requirements and a striking reduction in manual processes and paper-based components.

Conclusions

The implementation of an e-billing system has streamlined the billing workflow, nearly eliminating paper from the process and significantly reducing the delay between DOS and DOP.

A Novel Strategy for Evaluating the Effects of an Electronic Test Ordering Alert Message

Jason M. Baron, Anand S. Dighe

Massachusetts General Hospital, Department of Pathology Boston, MA.

E-mail: jmbaron@partners.org

Content

Computerized provider order entry (CPOE) systems offer clinicians the ability to order laboratory tests electronically. Many CPOE systems support the display of test-specific ordering alert messages and institutions can leverage these alerts to implement changes in test ordering guidelines or policies. However, alerts may vary considerably in efficacy; a better understanding of the characteristics and mechanisms contributing to an alert's success is needed.

Technology

Our institutionally-developed CPOE system allows clinicians to electronically search for potential inpatient laboratory tests and order desired tests from among those retrieved. The system captures highly detailed data regarding user interactions.

Design

We utilize our detailed user interaction data to understand the mechanism by which CPOE alerts influence test ordering. In this report, we evaluate a CPOE alert created to support an institutional policy restricting creatine kinase MB (CKMB) testing to limited indications. This alert, displayed during CKMB ordering, noted the new policy and required clinicians to either cancel the order or enter an indication.

Results

As shown in Figure, orders for CKMB decreased rapidly following the implementation of the alert. Searches for CKMB-associated search terms also decreased significantly following the intervention. The percentage of successful CKMB searches not resulting in orders increased dramatically. These results demonstrate the effectiveness of our alerting strategy and provide insight into the mechanisms of alert efficacy.



Conclusions

The data we capture in the context of CPOE user interactions helps distinguish the value of an alert in providing just-in-time advice from its value in providing longer-term education. For example, since clinicians searching for CKMB but reconsidering in response to an alert log a search without an associated order, the percentage of searches not associated with orders is suggestive of the immediate advisory effects. Likewise, trends in total CKMB search volume provide an indication of the level of clinician education. Application of this analysis to a larger cohort of alerts may provide an understanding of which alert characteristics are most beneficial for different effects and may lead to the development of improved alert strategies.

Integration of Digital Gross Pathology Images for Enterprise-Wide Access

Milon Amin, Gaurav Sharma, Ralph Anderson, Brian J. Kolowitz, Anil V. Parwani, Rasu B. Shrestha, Liron Pantanowitz

University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, PA.

E-mail: aninm2@upmc.edu

Content

Sharing digital pathology images for enterprise-wide use into a picture archiving and communication system (PACS) is not yet widely adopted. Benefits of sharing PACS images in institutional multimedia repositories include amalgamation of clinical findings for patient care and education. We share our solution and three-year experience of transmitting such images to an enterprise image server (EIS).

Technology

Laboratory Information System (Cerner CoPath v.3.2 with PicsPlus image management system), Digital Cameras (Nikon DS-U2), Pathology Image Server (PicsPlus Server), EIS (Philips iSite v.3.5), Interface Engine (HL7-Message-Routing), Enterprise Digital Imaging and Communications in Medicine (DICOM) Wrapper v.1.5.



Design

Gross pathology images acquired by prosectors were integrated with clinical cases into the laboratory information system, and stored in JPEG2000 format on a local image server. Automated daily searches for cases with gross images were used to compile an ASCII text file that was forwarded to the institutional Enterprise DICOM wrapper server. Concurrently, an HL7-based image order for these cases was generated, containing the locations of images and patient data, and forwarded to the Enterprise DICOM wrapper, which combined data in these locations to generate images with patient data, as required by DICOM standards. The image and data were then "wrapped" according to DICOM standards, transferred to the PACS servers, and made accessible on an institution wide basis.

Results

In total, 26,966 gross images from 9,733 cases were transmitted from the laboratory information system to the EIS. The average process time for cases with successful automatic uploads (n=9,688) to the EIS was 98 seconds. Only 45 cases (0.5%) failed requiring manual intervention. Uploaded images were immediately available to institution-wide PACS users (Figure 1). Since inception, user feedback has been positive.

Conclusions

Enterprise-wide PACS-based sharing of pathology images is feasible, provides useful services to clinical staff, and utilizes existing information system and telecommunications infrastructure. However, shared images require a proper "DICOM wrapper" for multi-system compatibility. Development of this process requires significant programming skill and manpower. Although our methods were developed in-house, commercially available methods are emerging. Plans are underway to begin sharing digital microscopic pathology images with electronic health records and EIS at our institution.

Session-3

IVD / Molecular / Training

Wednesday, October 5, 2011 (7:30 am - 8:55 am)


Kings Garden South / LeBateau

Investigation of KOC Expression as a Potential Diagnostic Biomarker for Pancreatic Ductal Adenocarcinoma

Asif Ali 1 , Victoria Brown 2 , Jamieson 3,4 , S.M. Denley 3 , R.C. Carter 3 , C.J. McKay 3 , Karin A. Oien 1,5

1 Institute of Cancer Sciences, College of MVLS, University of Glasgow, Glasgow, 2 Department of Pathology, Forth Valley Royal Hospital, Larbert, 3 West of Scotland Pancreatic Unit, 4 University of Glasgow, Department of Surgery, 5 University Department of Pathology, Glasgow Royal Infirmary, Alexandra Parade, Glasgow,UK.

E-mail: a.ali@beatson.gla.ac.uk

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is common and aggressive with a 5-year survival of 2-3%. Initial assessment of patients involves imaging and diagnostic cytology at endoscopy. Pre-treatment diagnosis on cytology samples can be difficult to establish, and may be improved with diagnostic biomarkers. KOC (k homology domain protein) is highly expressed in PDAC but less in normal ducts. Therefore, KOC could help to increase the diagnostic accuracy of pancreatic ductal adenocarcinoma (PDAC) versus benign or inflammatory tissue. Our aim was to validate the expression of KOC in a local surgical cohort.

Material and Methods

Optimised antibodies for KOC were applied to 3 Tissue Microarray (TMA) slides containing a total of 256 cores (149 PDAC, 107 Normal Ducts) from 89 patients. Afterwards, we analysed the immunohistochemical expression of KOC with the intension of differentiating PDAC from normal pancreatic ducts. We selected cores for comparison purposes as negative, weak, moderate and strong for staining. The expression was visualised as a cytoplasmic stain of varying intensity and proportion in distiller 2.1. Results were quantitatively measured as a "weighted histoscore", taking into account both the intensity of staining and the proportion of cells being positive [Histoscore= (negative=0×%cells + weak=1×%cells + moderate=2×%cells + strong=3×%cells)].

Results

Immunohistochemical analysis of KOC expression showed heterogeneity of staining in PDAC but not in normal ductal tissues. Overall average percentage of KOC expressing cells across all cores in 3 TMAs for PDAC samples was 77.9% (range, 0%-100%), however in normal pancreatic ducts it was 0.32% (range, 0%-10%) [p <.0001, Independent sample t test]. Similarly, the average histoscore for PDAC samples was 153 (range, 0-300), while for normal ducts it was 0.52 (range, 0-18) [p <.0001, Independent sample t test]. Finally, with a cut-off of 12.5% positivity of cells and at least weak staining, a sensitivity of 83.9% and specificity of 100% was achieved.

Conclusion

The results of this study with 100% specificity and almost 84% sensitivity demonstrate that KOC expression is essentially restricted to PDAC in tissue samples. Thus it has the potential to increase the diagnostic accuracy of cytological samples of PDAC, but further studies on cytologic samples of PDAC and normal ducts are required.

Selected Hematologic Malignancies Show Interspersed Repeat Elements Clustering Near Chromosomal Translocations Breakpoints

Nemanja Rodic, Kathleen Burns 1

Johns Hopkins Hospital, Department of Pathology, Baltimore, MD, 1 McKusick-Nathans Institute of Genetic Medicine, Sidney Kimmel Comprehensive Cancer Center Throughput Biology Center, Baltimore, MD.

E-mail: nrodic1@jhmi.edu

Content

Chromosomal translocations are important to the development of hematologic malignancies, though their mechanisms are only partially understood. Some chromosomal translocations involve V(D)J-type recombination or selected sequences, such as CpG dinucleotides. However, most chromosomal translocations are thought to be random, presumed to be due to ionizing radiation of reactive oxygen species. A publically available database of selective recurrent chromosomal translocations breakpoints is maintained, though no bioinformatics pipeline exists for its evaluation with respect to interspersed repeats.

Technology

We are evaluating associations between recombination-promoting motifs, such as repeat elements, and chromosomal breakpoints by developing and applying a computational technique to a large publically available breakpoint database.

Design

We have analyzed a database of over 470 breakpoints from recurrent interchromosomal rearrangements in human hematopoietic tumors. We started by sequence alignment of each breakpoint to a unique genomic coordinate. Next we used pattern recognition software to visualize repeat element motifs distributions near chromosomal breakpoints. We then developed a computational approach to map and calculate distances between chromosomal breakpoints and nearest repeat element motifs. Finally, we applied formal statistical method to identify breakpoints that are closer to the motifs than they should be given random chance.

Results

Of nine breakpoint loci analyzed, we show that human translocation breakpoints at Transcription factor 3, C-abl oncogene 1receptor tyrosine kinase, and Myeloid/lymphoid or mixed-lineage leukemia variant gene loci show distinctive patterns of clustering in proximity to repeat elements. Organizing the breakpoints by the stage of development during which the rearrangement occurs reveals that the repeat element-type translocations occurred in the Pro-B/Pre-B Cell and Lymphoid-Myeloid Hematopoietic Stem Cells. Interestingly, we do not observe repeat element sequence hotspots in lymphoid progenitor, mature B, or T cells.

Conclusion

We show that chromosomal breakpoints cluster near repeat elements in translocations incurred at the Pro-B/Pre-B Cell and Lymphoid-Myeloid hematopoietic stem cell stage. The stage specificity and repeat element targeting may be related to locus specific epigenetic modifications within selected repeat element sequence domains.

Tumor Microenvironment Influences Glioblastoma Molecular Subclass and Transcription Factor Expression

Christina Appin 2 , Lee AD Cooper 1,4 , David A. Gutman 1,4 , Candace Chisolm 2 , Yuan Rong 2 , Tahsin Kurc 1,4 , Erwin G. Van Meir 3,5 , Joel H. Saltz 1,2,4,5 , Carlos S. Moreno 2,4,5 , Daniel J. Brat 2,4,5

1 Departments of Biomedical Informatics, 2 Pathology and Laboratory Medicine, 3 Neurosurgery, 4 Center for Comprehensive Informatics, 5 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.

E-mail: cappin@emory.edu

Content

Gene expression profiling has made possible the further subclassification of human malignancies, providing data that identifies new potential therapeutic targets. The Cancer Genome  Atlas More Details (TCGA) project, through cluster analysis based on gene expression, has demonstrated four distinct molecular subclasses of glioblastoma (GBM), designated proneural, neural, classical and mesenchymal. The mesenchymal class, associated with the worst prognosis, is regulated by six transcription factors, with C/EBP-β/δ and STAT3 identified as master transcriptional regulators. Our study investigates whether the tumor microenvironment influences GBM molecular subclass and master transcriptional regulator expression.

Technology

Digitized TCGA GBM frozen section slides were downloaded and areas of necrosis and angiogenesis were selected and quantified using a human-computer interface. Significance Analysis of Microarrays (SAM) and Cox regression were used to identify genes significantly correlated with microenvironment. Ingenuity Pathway Analysis was used to identify pathways enriched with necrosis-correlated genes.

Design

177 slides from 91 patients were analyzed. Extent of necrosis and angiogenesis were determined as percentage of total tissue. SAM and Cox regression analysis were used to identify genes correlated at 5% significance (with multiple hypothesis correction).

Immunohistochemistry was performed on a separate set of 10 GBM samples for the transcription factors C/EBP-β/δ, and STAT3.

Results

GBM samples with a high degree of necrosis were more likely to be of the mesenchymal class. Furthermore, the mesenchymal class had a higher mean percent necrosis than the other classes. Among non-mesenchymal classes, as extent of necrosis increased, the transcriptome more closely resembled that of the mesenchymal class. Angiogenesis did not show a significant correlation with transcriptional class. Cox regression analysis identified 2,422 genes correlated with extent of necrosis. The transcription factors C/EBP-β/δ, STAT3, FOSL2, bHLHE40 and RUNX1 (regulators of the mesenchymal class) were among those showing the tightest correlation with necrosis. Integrated Pathway Analysis of genes associated with necrosis identified enrichment of canonical pathways including hypoxia signaling, Rac, Rho, PI3K/AKT, NFkB, IL-6, ERK/MAPK, and JAK/STAT. Immunohistochemistry showed strong expression of C/EBP-β/δ, specific for the hypoxic, peri-necrotic "pseudopalisading" tumor cells.

Conclusion

This study demonstrates that necrosis is strongly associated with the GBM mesenchymal subclass and influences the expression of master transcriptional regulators C/EBP-β/δ and STAT3.

How do Pathology Residents Acquire Expertise in the Reading of Dermatopathology Slides?

Claudia Mello-Thoms

University of Pittsburgh, Department of Biomedical Informatics, Pittsburgh, PA.

E-mail: mellothomsc@upmc.edu

Content

There are many theories regarding how medical residents acquire expertise in Pathology. We will focus on two theories, the 'forward reasoning' strategy, which advocates that identification of diagnostic criteria is paramount to the formation of correct diagnostic hypotheses, and the 'hypothetical-deductive' model, which poses that residents first generate a number of possible diagnostic hypotheses and then extract diagnostic criteria in order to confirm or to dismiss the generated hypotheses.

Technology

A custom-designed interface was used for this study. Observers had the ability to zoom in on the slides (up to 20x), pan, report diagnostic criteria, diagnostic hypotheses and final diagnoses (or set of differential). All interactions with the interface were time-stamped and recorded.

Design

Eleven Pathology residents read a set of 20 virtual slides depicting inflammatory skin dermatitides. Artificial Neural Networks were trained to represent the decision making strategy of the residents. Under this paradigm, four different types of models were built: (i) using identified diagnostic criteria to predict correctness of recently identified diagnostic criteria; (ii) using reported diagnostic hypotheses to predict correctness of identified diagnostic criteria; (iii) using reported diagnostic criteria to predict correctness of recently identified diagnostic hypothesis; and (iv) using reported diagnostic hypotheses to predict correctness of recently identified diagnostic hypothesis. If residents are relying on the 'forward reasoning' strategy, models (i) and (iii) will be better predictors than models (ii) and (iv), respectively. The reverse will be true if they are using the 'hypothetical-deductive' model.

Results

Preliminary analyses suggest no statistically significant differences in prediction between models (i) and (ii). However, significant differences seem to occur between models (iii) and (iv), with model (iii) (using identified diagnostic criteria to predict correctness of newly reported diagnostic hypothesis) being a stronger predictor (average area under the ROC = Az = 0.820) than model (iv) (average area under the ROC = Az = 0.776). Statistical analyses were carried out using the Mann-Whitney U-test, P<0.05.

Conclusion

Connectionist modeling has been used extensively to explain cognitive processes in many domains. Here we apply it for the first time to identify decision making patterns among Pathology residents.

Facilitating Feedback and Education on the Hot Seat Rotation

John H. Sinard, Neil Mutnick,

Peter Gershkovich

Yale University School of Medicine, Department of Pathology, New Haven CT.

E-mail: john.sinard@yale.edu

Content

The "Hot Seat" rotation in anatomic pathology residency training gives senior residents the opportunity to review a large volume of slides from a variety of services and to field clinician inquiries about the cases. Traditionally, obtaining feedback on those cases that they have seen has been difficult to ensure, and residents have often resorted to making lists of interesting cases and looking up these cases days later in the anatomic pathology laboratory information system (AP-LIS) to see how the attending pathologist ultimately signed the case out.

Technology

We developed in-house a custom software solution that is semi-integrated into the operation of our CoPath (Cerner DHT, Waltham MA) information system. The software is written in Java and deployed as a web application using the Google Web Tool Kit.

Design

The Hot Seat application is designed to provide: 1) rapid access to all of the pertinent clinical and ancillary information about a case (text, histology status, events, clinician contact information, photographs, prior specimens, etc.), thus, replacing the need for the working draft; 2) an opportunity for the resident to enter their impression of the case; 3) the ability for the resident to compare (later and efficiently) their impression with the signed out final diagnosis, and to self-score the level of agreement; and 4) summary statistics of the resident performance by specialty area for self evaluation.

Results

The application has been extremely well received by the residents on the rotation. Resident evaluation of the rotation has improved, and the residents feel they can look at more cases more efficiently than the prior method of flipping through pages in a logbook. Also, because the interface allows rapid access to complete information about a case, it has begun to be used outside of the hot-seat rotation.

Conclusions

Informatics tools can be used to improve the educational experience of residents on a hot seat rotation by tracking cases, providing feedback on diagnosis, and enabling self-assessment of performance.

Optimizing Pathology Teleconferencing in the Disbursed Academic Medical Setting: Image Quality, Flexibility, and Cost Considerations Differentiate Options

Philip J. Boyer 1 , Lisa Litzenberger 1 , Brandon Davis 1 , Andrew B. Sholl 1 , Frank Moore 1 , Andrew J. Rohrer 1 , Mark L. Gallen 1 , Fernando J. Castro-Silva 1 , Francisco G. LaRosa 1 , Geza S. Bodor 2

1
University of Colorado Denver, Department of Pathology, Aurora, CO, 2 Denver Veterans Affairs Hospital, Denver, CO.

E-mail: philip.boyer@ucdenver.edu

Content

The University of Colorado Denver (UCD), department of pathology faculty, residents, and fellows are dispersed among six training sites, necessitating a teleconferencing solution for inter-site conferences and meetings. A polycom distributed media application system was in use, provided by UCD educational support services, requiring the use of a complex, expensive hardware solution in primary conference rooms with meetings established and maintained by UCD staff, operated through a "bridge," with staff juggling multiple concurrent conferences. Virtually every Polycom session was plagued by unacceptably poor image quality and delays in or failure of transmission of images, with frequent dropped connections. Three of our sites do not have the hardware in place to accommodate such conferencing. Departmental faculty and staff were not in control of the process.

Technology

Evaluations on the UCD campus and, when possible, between teaching sites were undertaken with (1) combined hardware and software solutions including Polycom, Haivision, and LifeSize options and (2) online software / conference call solutions including GoToMeeting, Adobe Connect, and WebEx.

Design

The various options were assessed for simplicity of use including working within the VA system's locked-down constraints, reliability, quality of transmitted images and sound, flexibility including option to easily switch between presenters at different sites during a conference, ability to quickly create an unscheduled conference, ability to incorporate live transmission of whole slide images and microscopic slides, conference archiving, and cost.

Results

The aging Polycom equipment at two sites would not accommodate the transmission of high definition signal, budget would not allow for replacement, and three sites did not have the equipment to receive the Polycom conferences. The budget for a replacement multi-featured hardware-software system was not available. The online software / conference call solutions were similar, each with positives and negatives.

Conclusions

A combination of a GoToMeeting online session and a concurrent conference call was found to be the least complex option that allowed for outstanding image quality, easy alternation of presenters between sites, and minimal cost. Connections at each of the sites were easily accomplished by residents and departmental staff, for scheduled and ad hoc meetings, and all six sites could easily join in on conferences.


   Scientific Session Top


Session-1

Imaging & Computational

Thursday, October 6, 2011 (7:30 am - 8:55 am)


Grand Ballroom 1

3D Prostate Histology Reconstruction Informed by Quantified Tissue Cutting and Deformation Parameters

Eli Gibson 1 , Cathie Crukley 1,2 , José A. Gómez 1 , Madeleine Moussa 1 , Glenn Bauman 1,2 , Aaron Fenster 1,2 , Aaron D. Ward 1

1
The University of Western Ontario, Robarts Research Institute, London, Ontario, Canada, 2 Lawson Health Research Institute, London, Ontario, Canada.

E-mail: egibson@imaging.robarts.ca

Content

3D reconstruction of digitized 2D histology sections sparsely sampled from grossed tissue blocks depends on knowledge about the position, orientation and deformation of tissue during histological processing. Many 3D reconstruction methods make the assumption that histology sections are taken from equally spaced, parallel planes at the front faces of tissue blocks. This work quantified aspects of histological processing and applied the results to inform the design of a reconstruction algorithm that aligns histology to ex vivo magnetic resonance (MR) images.

Technology

We acquired MR images with 0.27×0.27×0.20mm voxels using a 3T Discovery MR750 (GE Healthcare, Waukesha, USA), and histology images with 30x30μm pixels using a ScanScope GL (Aperio Technologies, Vista, USA) bright field slide scanning system. Statistical analysis was performed using Prism 5.04 (Graphpad Software, Inc., San Diego, USA). We developed the 3D reconstruction using MATLAB 7.8.0 (The Mathworks Inc., Natick, USA).

Design

MR images of 7 radical prostatectomy specimens were acquired before and after gross sectioning into 4.4mm tissue blocks. One section taken from each block was stained and digitized. 7-15 homologous landmarks per midgland section (204 in total) were identified on MR and digitized histology images. Positions and orientations of sections within the tissue blocks were calculated using the best-fit plane to landmarks identified in MR images, and 4 deformation models (rigid, rigid+scale, affine, and thin-plate-spline) were assessed by aligning homologous fiducials using each model and subsequently measuring misalignment of landmarks using a leave-one-out cross-validation. These quantifications informed the design of a 3D reconstruction algorithm to place histology in the context of the MR images, which was evaluated using homologous landmarks.

Results

Histology sections had a mean±std depth of 1.0±0.5mm and orientation of 1.7±1.1°. Rigid, rigid+scale, affine and thin-plate spline deformation models yielded mean±std misalignment of 1.4±0.7, 0.6±0.3, 0.5±0.3 and 0.4±0.3mm, respectively. The 3D reconstruction yielded a mean±std target registration error of 0.69±0.36mm.

Conclusions

Variability in the position and orientation of sections within tissue blocks could contribute substantial (>2mm) 3D reconstruction error. The deformation models for 3D reconstruction more flexible than rigid+scale yielded small improvements in accuracy (<0.2mm). Our 3D reconstruction algorithm achieved sub-millimeter(0.69mm) reconstruction error.

DICOM Compliant Histopathology Software

Danoush Hosseinzadeh 1,3 , Anne L. Martel 1,2,3

1
Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, Canada, 2 University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada, 3 PathCore Inc., Toronto, Ontario, Canada.

E-mail: dan.zadeh@pathcore.ca

Content

Recent advancements in high resolution whole slide scanners and the DICOM standard will spur a wave of modernization in pathology. Just as whole slide digital scanners are becoming available from several vendors, the DICOM standard has also been amended to include pathological imagery. The latter has the potential to affect pathology much like it has done for radiology. This paper discusses newly developed software that implements DICOM for histopathology images and discusses the changes in DICOM which have allowed the realization of such software.

Technology

The DICOM standard recently defined two supplements specifically for pathology: DICOM supplement 122 which deals with the particularities of pathological samples (tissue processing, specimen information, etc.) and DICOM supplement 145 which standardizes storage and data access methods to overcome the challenges of high resolution histological images.

Design

Adoption of DICOM in pathology can simplify the workflow for Pathologists. Current day workflows require Pathologists to physically sign out and handle slides. These challenges can be overcome by DICOM since it enables viewing and management of digital slides from any location using computers. Tele-pathology for instance could help many smaller hospitals which do not have resident pathologists and it would allow Pathologists to review cases away from the lab. Automated computer algorithms could also be used to assist Pathologists in a variety of tasks such as tumour margin estimation and disease grading.

Results

Software has been developed which creates histopathology DICOM images. The software works with whole slide scanners and can also be operated manually by lab technicians. It produces DICOM files containing all the meta-information available about the digitized slide (tissue processing steps, specimen collection processes, specimen type, sampling methods, stains, fixatives and more). Like other DICOM images, patient, study, and imaging parameters are also embedded in the file.

Conclusions

Digital pathology enables the conveniences of modern technologies. Recent availability of whole slide digital scanners along with recent supplements in DICOM have made advances in clinical pathology possible. We have developed software that creates DICOM compliant histological images to promote adoption of digital pathology.

We acknowledge support from the Ontario Institute of Cancer Research (OICR).

Efficacy Studies Investigating the Use of a Tablet PC to Perform Image Annotations on Digitized Pathology Specimens

Evita T. Sadimin, Wenjin Chen, David J. Foran

UMDNJ - Robert Wood Johnson Medical School, Department of Pathology and Laboratory Medicine, Center for Bioimaging and Informatics, New Brunswick, NJ.

E-mail: sadimiet@umdnj.edu

Content

In modern pathology imaging, the task of precisely tracing the boundaries of cells and other objects of interest is required for performing annotations of specimens, establishing gold-standard image archives for educational and training purposes and for preparing ground-truth training sets to test new quantitative imaging algorithms in computer vision research applications such as segmentation and classification. Given the potential impact of inaccurate renderings, our team has performed a systematic performance study to investigate the efficacy of using a commercial, off-the-shelf tablet to perform these annotations.

Technology

The onscreen interactive capabilities of tablets provide a much more intuitive interface for end-users when compared to conventional keyboard and mouse. In this study we explore the feasibility of tracing computer-generated geometric shapes exhibiting well-defined spatial characteristics and a range of salient biological objects by comparing tracing accuracy and repeatability of a standard stylus and mouse.

Design

The first experiment utilized a team of volunteers who were asked to trace 1-pixel-wide outlines of angular (triangle and nonagon) and curved (circle and ellipse) shapes. Each shape was retraced at three different scales. A Java based program was developed to record the tracing time and the coordinates of the traced boundaries. Tracing accuracy is measured by computing differences between the generated and traced contours as well as relative error in shape measurements. In the reproducibility experiment, several medical professionals were asked to precisely outline a well-defined microscopic image region five times.

Results

Preliminary results showed that tracing the images with stylus was not only significantly more accurate in all measurements than using mouse (p<0.05); it was also significantly faster (p=5e-11). The stylus also reduced error in tracing perimeter by 12%. In addition, tracing with stylus was more reproducible compared to mouse (p<0.05). Our results also indicate that it is possible to achieve optimum combination of speed and accuracy by selecting the optimum magnification in annotating pathology images.

Conclusion

We conclude that medical annotation using stylus is not only feasible but also more intuitive, accurate and reproducible than using mouse. Further work in this area will include implementation of tablet-based pathology annotation applications and better post-processing techniques to improve shape fidelity.

Development of Multigene Expression Signature Maps at the Protein Level from Digitized Immunohistochemistry Slides

Stephen C. Schmechel 2,3 , Gregory J. Metzger 1 , Stephen C. Dankbar 2 , Jonathan Henriksen 2,3 , Anthony E. Rizzardi 2 , Nikolaus K. Rosener 2

Departments of 1 Radiology and 2 Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 3 BioNet, University of Minnesota, Minneapolis, MN.

E-mail: schme004@umn.edu

Content

Molecular classification of diseases based on multigene expression signatures is increasingly used for diagnosis, prognosis, and prediction of response to therapy. Immunohistochemistry (IHC) is an optimal method for validating expression signatures obtained using high-throughput genomics techniques since IHC allows a pathologist to examine gene expression at the protein level within the context of histologically interpretable tissue sections. Additionally, validated IHC assays may be readily implemented as clinical tests since IHC is performed on routinely processed clinical tissue samples. However, methods have not been available for automated n-gene expression profiling at the protein level using IHC data. We have developed the methods to compute expression level maps (signature maps) of multiple genes from IHC data digitized on a commercial whole slide imaging system. Areas of cancer for these expression level maps are defined by a pathologist on adjacent, co-registered H&E slides allowing assessment of IHC statistics and heterogeneity within the diseased tissue. This novel way of representing multiple IHC assays as signature maps will allow the development of n-gene expression profiling databases in three dimensions throughout virtual whole organ reconstructions.

Technology

A software interface, which will be referred to as SigMap, was written in the Java programming language, generated IHC signature maps through a multistep image analysis and image registration process.

Design

Unstained sections of formalin-fixed, paraffin-embedded prostate tissue containing discrete areas of prostatic adenocarcinoma of different histologic grades were obtained with approval from the University of Minnesota Institutional Review Board. Six adjacent 4 micron sections were cut from a tissue block. One section was stained with hematoxylin and eosin (H and E). IHC was performed for MKI67, ENO2, CD34 and ACPP and alignment and protein expression with IHCMap was computed.

Results

The study pathologist created annotations of prostate cancer areas by Gleason grades present in the block, separately annotating 3+3, 3+4 and 4+3 areas within different virtual planes ("layers") of the reference slide image file. Additional information used by the software included a table of IHC stains and their respective user-input weighting factors. In this study, the weights for MKI67, EN02, CD34 and ACPP were chosen as 0.473, 0.035, 0.035 and -0.014, respectively. The sign of the weights reflects the current understanding as to each protein's up- or down-regulation in aggressive prostate cancer, but the current magnitudes of the weights are somewhat arbitrarily chosen to provide a proof a concept.

Conclusion

SigMap is a unique approach to multiplexed analysis in IHC, and uniquely leverages whole slide imaging. We successfully developed this method and applied it to a prostate cancer signature. Work is ongoing to determine utility in a larger clinical dataset.

In Silico Analysis of Diffuse Gliomas Identifies Microenvironmental Influence on Key Transcription Factors and Morphological Signatures of Glioblastoma

Lee A.D. Cooper, Jun Kong, Fusheng Wang, David A. Gutman, Sharath Cholleti, Tahsin Kurc, Carlos S. Moreno, Daniel J. Brat, Joel H. Saltz

Emory University, Center for Comprehensive Informatics, Atlanta, GA.

E-mail: lee.cooper@emory.edu

Content

Emerging multi-modal datasets that link histology to genetic and patient endpoints are creating new frontiers for pathology research. Using data from The Cancer Genome Atlas (TCGA) and REMBRANDT projects, we have developed In Silico methods and informatics tools to investigate the role of tumor microenvironment on transcription and the associations of histology and genetics on patient outcome. We have identified both microenvironmental influences on the expression of key transcription factors and the existence of morphological subtypes of glioblastoma.

Technology

Whole slide imaging presents opportunities to quantitatively study morphology at large scales. We have developed a suite of image analysis tools to segment and characterize millions of nuclei in gliomas. These tools generate statistical models of patient morphology that can be analyzed for comparison with patient outcome and genomics. We have also investigated necrosis in gliomas using a human-computer interface to identify necrotic tissue. Extent of necrosis can then be compared with gene expression arrays using Significance Analysis of Microarray to identify genes significantly correlated with necrosis. All segmentation and markup data are managed through the Pathology Analytical Imaging Standards database.

Design

Percentage of necrosis was analyzed in whole slide images of frozen TCGA GBM tissues. Percentage necrosis was correlated with gene expression to identify transcripts that are significantly correlated with extent of necrosis in 177 slides from 91 patients. The morphologies of 200 million nuclei were analyzed in images of permanent TCGA GBM tissues from 162 patients. Nuclear morphology was aggregated into patient-level profiles that were clustered to identify groups of patients with similar morphology. Patient outcome and genetic alterations were analyzed across clusters to determine cluster characteristics.

Results

The transcription factor CEBP-B/D, known for its role as a master regulator of the aggressive Mesenchymal GBM phenotype, was identified as significantly correlated with extent of necrosis. Immunohistochemistry analysis revealed that CEBP-B/D are hypoxia inducible, suggesting that GBM phenotype may be a local phenomenon driven by tumor microenvironment. Morphological analysis of nuclei revealed several patient clusters.

Conclusions

We have developed a suite of bioinformatics tools for multi-modal glioblastoma data analysis and integration and identified morphological signatures of glioblastoma and microenvironmental influence on key transcription factors.

Session-2

Decision Support - Natural Language Processing

Thursday, October 6, 2011 (7:30 am - 8:55 am)


Kings Garden North

A Clinically Intuitive, Non-Parametric Method Using Multidimensional Polyhedrons to Combine the Results of Multiple Laboratory Tests and Potential Implications for Clinical Laboratory Decision Support

Brian H. Shirts 1 , Sterling T. Bennett 1,2 , Brian R. Jackson 1, 3

1
University of Utah, Department of Pathology, Salt Lake City, UT, 2 Intermountain Healthcare, Salt Lake City, UH, 3 ARUP Laboratories, Salt Lake City, UT.

E-mail: brian.shirts@hsc.utah.edu

Content

Realizing the potential of personalized medicine will require statistical methods to integrate traditional laboratory data with genetic and clinical information for diagnosis and risk prediction. Many methods of multivariate analysis have been applied to diagnostics, but they are practically opaque and none has been widely adopted. We evaluate the method of counting disease and non-disease cases in multidimensional polyhedral partitions of the multivariate result space to calculate likelihood ratios and probabilities of diagnosis. In principle, this method is a non-parametric analog of multivariate Gaussian-based likelihood ratios used for maternal serum screening.

Technology

Simple tables of clinical data were used with each parameter defining a separate dimension in a multidimensional clinical data space. We used R statistical software to evaluate the distribution of cases and controls near specific points in this multidimensional space defined by a specific set of patient test values.

Design

We generated multidimensional polyhedrons, centered on specified test values and extending a specified multiple of the median average deviation from this center for each testing dimension. Counts of cases and controls contained in this polyhedron defined the probability of the 'patient' being a case or control. We used a sample of 2053 individuals with celiac disease workup at Intermountain Healthcare to illustrate potential utility in improving decision support information provided to clinicians and preventing unnecessary biopsies.

Results

tTG IgA and age were important predictors of biopsy positivity with sufficient data for subsequent analysis. 1652 individuals in our clinical sample had both of these measures. Probability of a positive biopsy ranged from 0 to 1. Accuracy of prediction varied with the density of past data near the test values, with median difference between upper and lower 95% confidence limits being 0.11.

Conclusions

The presented method for multivariate analysis of clinical results is transparent, conceptually simple, and provides results that are easy to interpret. A limitation of this method is the requirement of very large data sets when many parameters are used. An advantage is that a diagnostic laboratory could continuously integrate data from local clinical encounters into prediction databases, enabling more precise probability estimates that are tailored to the local population.

Design and Implementation of Custom Middleware Based Chemistry Lab Autoverfication Rules

William J. Lane, Frank Kuo, Neal Lindeman

Brigham and Women's Hospital, Pathology Department, Boston, MA.

E-mail: wlane@partners.org

Content

The accuracy of clinical laboratory test results must be verified before release. Verification is intended to detect analytical errors, by comparing the results with expected values in both health and disease. In many laboratories, this is done manually by medical technologists, at great labor cost and with varying degrees of expertise. Alternatively, a computer may be programmed for automated review (autoverification) of results.

Technology

The Chemistry Lab at Brigham and Women's Hospital (BWH), which performs ~4.5 million per year, recently implemented autoverification of results generated on Cobas 6000 Analyzers (Roche Diagnostics, Indianapolis, IN), using middleware (Data Innovation, South Burlington, VT) that connects to a legacy LIS.

Design

For each analyte, an autoverification rule decision tree was designed based on knowledge of that analyte in health and in disease. The rules were simulated using real patient data accrued over one month. When needed, rules were adjusted and re-simulated. Rules that passed the simulation were encoded in middleware and tested in silico with "cases" of results designed to assess the performance of the rules. Once all testing was complete, rules were implemented and monitored in production for several days.

Results

Analyte-specific autoverification hold rules were created that identify if a particular result should be held. The analyte-specific approach allowed piecemeal deployment of rules for each analyte (most common analytes first). The rules evaluate delta checks (difference between two successive measurements of the same analyte in the same patient), instrument error flags, values >3SD beyond the population mean, and values inconsistent with other analytes assessing complementary states of disease or health in a given patient. Currently, 13 different rule prototypes are used, for 48 analytes. In the absence of hardware errors detected by the instrument, these rules autoverify 95% of analyte results and 85-90% of all chemistry tests, resulting in a significant savings in labor and cost. Rules for the remaining analytes are in development.

Conclusions

Custom chemistry analyte autoverification rules were developed and implemented in middleware, enabling a significant savings in labor costs for the laboratory. These rules should be usable by other institutions after adjusting the rule parameters to match their own patient populations.

Making Malarial Diagnosis More Reliable: Using Image Analysis for Identification of Plasmodium Falciparum Gameotcytes

Joy J. Mammen 1 , Maqlin P. 2 , Feminna Sheeba 2 , T. Robinson 2

1
Christian Medical College, Transfusion Medicine, Vellore, 2 Madras Christian College (Autonomous), Tambaram, Chennai, India.

E-mail: joymammen@cmcvellore.ac.in

Content

Malaria is a significant cause of morbidity and mortality in tropical countries. According to WHO, in 2009, more than 50% of confirmed reported malaria cases were from India. The gold standard for the diagnosis of malaria continues to be the manual microscopic examination of a stained thick smear or thin smear where at least 100 fields should be screened at 100x (oil immersion) with at least 8-10 minutes spent per slide. Given the high prevalence the numbers for primary screening and quality assurance (10-15% repeat screening) is a mammoth task requiring scarce resources. Therefore there is a fear of underreporting and difficulty in quality control of positive cases. Using technology to assist in screening of slides by image analysis will introduce a paradigm shift in the current scenario.

Technology

MATLAB 2009b (MathWorks Inc, MA, USA)

Design

In India, the common species seen are Plasmodium falciparum and Plasmodium vivax. Automatic segmentation techniques were applied to tiff images of peripheral blood smears acquired using Leica DFC camera, in order to identify gametocytes. To identify the gametocytes, as a first step, the gray image of the source image were inversed and converted into a binary image with a proper threshold value, in order to obtain all the objects in the image (I 1 ). The objects other than WBCs and RBCs are eliminated to obtain image I 2 . The difference between images I 1 and I 2 is obtained. The application then used morphological operations and granulometric analysis to segment out only the gametocytes. The number of segmented gametocytes is also obtained from the segmented binary image.

Results

We have a prototype application that can identify p. falciparum gametocytes. The results of the preliminary validation study will be discussed. The quality of the images and the presence of artifacts affects the analysis and these issues should be taken in order to obtain better results.

Conclusions

The above data shows that the possibility to use image analysis techniques for screening of blood smears for malaria parasites is possible. More work is required to refine the algorithms and the methods used. Initially this technique may be used for quality control.

Extraction and Analysis of Data Elements from Text-based Prostate Cancer Pathology Reports

Kavous Roumina, Eugene Farber, Walter H. Henricks

Cleveland Clinic, Center for Pathology Informatics, Cleveland, OH.

E-mail: roumink@ccf.org

Content

Pathology reports in laboratory information systems are inherently textual and do not easily lend themselves to data mining activities. The capability to extract discrete data elements from text-based pathology reports would be of great value for research and analysis. We describe a heuristic-based approach to categorize and compartmentalize prostatectomy cancer reports into discrete data elements ready for further analysis.

Technology

Data analysis component (.NET Framework 3.5, Microsoft); relational database (Access 2003, Microsoft); laboratory information system (CoPathPlus, Cerner).

Design

The system consists of two components: extract/analysis and presentation modules. The extract/analysis module identifies Key-Value pairs from textual, checklist-formatted prostatectomy reports extracted from the laboratory information system. Keys are checklist headers, e.g. "Gleason Score". Values are respective observations in the report, e.g. "7". The system analyzes Keys and Values, extracts pertinent Values, and assigns them to Keys as discrete elements in the database. The logic accounts for variations in the tumor report checklist over the years analyzed. Employing object-oriented design, Key-Value pairs are organized as reusable programming codes ("classes"). The system presents the Key-Value pairings to a reviewer who verifies assignments by the system and resolves potentially inaccurate matches resulting from ambiguities in the source report. Each Key-Value pair is assigned a color-coded level of "uncertainty". The reviewer may access the original report within the application. Following review, the user "commits" the case to the permanent database.

Results

The system has processed 3456 historical prostatectomy reports (2003-2011) from the laboratory information system. Use of the system has transformed the text-based, non-discrete diagnostic and staging data in these reports into discrete data elements available for analysis and research. A typical prostatectomy report contained 28 Key-Value pairs. An average of 6.1 Key-Value pairs per report (<25%) required modification by the user prior to commitment to the database.

Conclusion

A simple yet robust, object-oriented system has enabled the transformation of textual diagnostic, staging, and prognostic data in prostatectomy pathology reports into discrete data elements to enable clinical and translational research and other analyses. The design paradigm should be deployable to other types of textual checklist-formatted pathology reports.

Advantages of Structured Data Reporting Using the CAP Electronic Cancer Checklists (eCC): The Cancer Care Ontario Experience

Samantha Spencer 1 , Gemma Lee 2 , Jaleh Mirza 1 , John R. Srigley 2,3 , Tim Yardley 2 , Aleem Bhanji 2 , Jeffery Karp 1 , Gregory Gleason 1 , Richard Moldwin 1

1 The College of American Pathologists, Deerfield, IL, 2 Cancer Care Ontario, Toronto, Ontario, Canada, 3 McMaster University, Hamilton, Ontario, Canada.

E-mail: sspence@cap.org

Content

A standard informatics approach for recording and reporting cancer pathology reports has the potential to prevent diagnostic errors and omissions, thereby improving patient care and research. To this end, the College of American Pathologists produces the electronic Cancer Checklists (eCC) based on the CAP Cancer Protocols, widely-recognized as a gold standard in cancer pathology data collection. The eCC informatics model allows for standardized data transfer from anatomic pathology software to central cancer registries.

Technology

Checklist questions and answers are entered into an editing tool for storage in a SQL Server database. Each checklist is exported as a single XML file from the eCC database. Vendors use these XML files to create standardized data-entry forms and reports for pathologists. The standardized eCC codes stored in the vendor database can be sent to central registries, using HL7 messages for mandated cancer reporting.

Design

Cancer Care Ontario has adopted the eCC into its cancer registry data collection system to improve interoperability and the quality of data collection for cancer surveillance. Error reduction and increased timeliness are additional factors driving eCC uptake. For 2011/2012, Cancer Care Ontario has mandated implementation of 63 eCC templates, involving 110 pathology laboratories throughout the province.

Results

As of August 2011, 90/110 hospitals (82%) have implemented eCC-based synoptic reporting. Ten to fifteen additional hospitals are slated to participate by late 2011. In July 2011, nearly 75% of cancer pathology resection reports were sent to the central registry using the eCC model. A survey of 970 clinicians found that pathologists, surgeons and oncologists expressed high satisfaction with the eCC-based reports compared to traditional narrative reports. The adoption of the eCC has led to more complete reports, as well as the automated capture of cancer staging and related data. Detailed reports are shared with hospitals to provide feedback on workflow and to assist with quality assurance efforts.

Conclusion

The Cancer Care Ontario eCC integration experience is an informatics success story. It demonstrates that comprehensive implementation of eCC-based standardized structured reporting improves information system interoperability, data reporting, quality assessment, cancer research and cancer care.

Evaluation of a Natural Language Processing Platform in Concept Tagging of Surgical Pathology Reports for Information Retrieval

Radhika Srinivasan 1 , Albert Riedl 1 , Estella Geraghty 2 , Michael Hogarth 1,2

1 UC Davis School of Medicine, Departments of 1 Pathology and Laboratory Medicine and 2 Internal Medicine, Sacramento, CA.

E-mail: rsrinivasan@ucdavis.edu

Content

Diagnoses in surgical pathology reports are primarily contained in narrative, "free text" sections that limit the ability to implement concept-based searching. This work evaluates MojoMapper, a Natural Language Processing (NLP) framework, in the task of concept-tagging biomedically relevant concepts in surgical pathology reports to support searching cases by concept.

Technology

MojoMapper is a java-based, web services-oriented NLP platform developed at UC Davis. It implements stochastic and rule-based text processing that adjusts behavior in response to semantic and syntactic features of the input text. The architecture is pipeline-based with annotators operating on pre-processed text for linguistic manipulation, parts-of-speech discrimination, negation detection and determination of semantic type.

Design

To have the broadest concept coverage possible, we configured MojoMapper to use the Unified Medical Language System. We extracted 232 diagnostic phrases from 100 sequential pathology reports. Phrases only containing temporal concepts ("cycle day 24-25"), lacking biomedical concepts ("see comments", "no further findings", "histologic grade, low grade"), or conceptual content of low retrieval value ("negative surgical margins") were excluded from scoring resulting in 215 phrases used to evaluate performance. Two physicians (M.H. and E.G.) evaluated the performance of the system. Individual points were awarded for each correctly identified disease relevant concept and negation of concept.

Results

MojoMapper correctly identified 82% relevant concepts. Inter-rater reliability between the two physicians was moderate to good (kappa 58%). In analyzing the MojoMapper errors, we identified a number of optimizations that will improve the system's ability to correctly concept-tag biomedical concepts for information retrieval of surgical pathology cases.

Conclusions

MojoMapper was built to concept-tag causes of death in electronic death records and was used as is without any surgical pathology optimizations. Given this we find that this system is still able to correctly match a high percentage of pathology concepts. Using MojoMapper's architecture to integrate new annotators, we plan to add pathology annotators to address many of the pathology lexicon specific issues that caused matching failures in the current analysis. We also plan to implement improved semantic processing so that "presence of inflammatory cells" is conceptually equivalent to "presence of an inflammatory process".

Session-3

Lab Automation

Thursday, October 6, 2011 (7:30 am - 8:55 am)


Kings Garden South/LeBateau

Automation of Parasitized Erythrocyte Count by Microorganisms in Wild Animals

Denise F.P. Costa, Leonilda Santos, Fabiana Peres

State University of West of Paraná, Engineering and Science, Foz do Iguacu, Brazil.

E-mail: denise.costa2@unioeste.br

Content

To keeping the biodiversity of wildlife is required to check the presence of microorganisms on the surface of erythrocytes can cause anemia if the animal is with impaired immune systems. The wild animals in captivity, be influenced by stress and due to their behavior, many of the diseases can be diagnosed only by laboratory tests. The quantification of microorganisms is performed manually and this activity is an exhaustive, time consuming and more error-prone, depends on physician skill. In order to facilitate this activity, a procedure is being developed using techniques of Digital Image Processing to perform the quantification of microorganisms automatically.

Technology

Blood samples of wild animals are collected with anticoagulant and examined fresh; the capture of images is made using a microscope Olympus BX-41, objective 40 x and eyepiece 10 x, an Olympus DP-12 digital camera coupled to the biological microscope and the camera software to transfer images to the computer via USB 2.0 for application of the techniques of Digital Image Processing.

Design

After defining a protocol for capturing images of Digital Image Processing techniques are applied to classify the constituent objects. Through a representation and description to put in evidence the characteristics of the objects of interest will be held the counting of each class: total erythrocytes and microorganisms, being defined the percentage between the quantitative constituent objects.

Results

The automated counting of cells by Digital Image Processing facilitates the work of professional in the field of hematology, to be effective, accurate and fast, reducing costs to the laboratory. Upon completion, the final product will be used to assess the interference of parasitic microorganisms in erythrocytes in relation to anemia, which interferes with the biodiversity of local fauna.

Conclusion

The discovery of hemotropics microorganisms in wild animals is recent, development manual techniques, and the development of innovative automated quantification of microorganisms parasites of erythrocytes. The monitoring of parasitic microorganisms is important in maintaining a healthy population of wild animals which, in turn, helps in reducing losses to the species, avoiding the imbalance of regional biodiversity.

Application of Tracking Technology in Anatomic Pathology

Troy Brown, James Dobbs

Orion Biosystems, Rolling Meadows, IL.

E-mail: troy.brown@orionbiosystems.com

Content

Misidentification errors in the anatomic pathology laboratory, while relatively infrequent, can have disastrous consequences. Such errors can cause patient inconvenience or harm when additional tissue collection is needed. Misidentification of cases, specimens, blocks and slides can delay diagnosis and treatment or cause treatment to be administered inappropriately. Technology solutions such as barcode labeling and tracking are being used but have not been fully developed. This paper describes misidentification errors and possible technology solutions.

Technology

We analyzed the use of relational databases and barcoding in pathology laboratories. We also studied the application of Lean and Six Sigma technologies in the pathology laboratory. We studied the current and potential effectiveness of electronic cross-checking and electronic tracking systems using Standard Query Language databases.

Design

We conducted a review of current literature regarding misidentification of cases, specimens, blocks and slides in pathology laboratories. We focused on specific vulnerabilities associated with the anatomic pathology laboratory setting, and potential remedies for each. We reviewed the use of barcode technology in all types of laboratories, including anatomic pathology.

Results

Barcode technology is well-established in a number of health care settings, including laboratories. Some anatomic pathology laboratories use barcode technology, but it is not fully integrated, often requiring the use of handwriting at the point of tissue collection and accessioning. Many anatomic pathology laboratories rely on an unintegrated, multi-tiered and nonsynchronous approach to maintaining quality and integrity throughout the tissue handling process. Paper requisition forms, which can be lost or placed with the wrong tissue, are still used.

Conclusions

Anatomic pathology laboratories are particularly vulnerable to misidentification errors because tissue undergoes several processes from the time of collection through transcription. Anatomic pathology laboratories would benefit from a barcode system that tracks tissue from the time of collection through transcription. Such a system would reduce human error and identify misplaced tissue. A paperless requisition system would also reduce misidentification errors by reducing the potential for misplaced requisition forms and errors related to handwritten information.

Deployment of an Orders Interface Between CoPathPlus and an Automated Immunoperoxidase Staining Platform

J. Mark Tuthill, Michael Czechowski, Kathleen M. Roszka, Mehrvash Haghighi

Henry Ford Hospital, Division of Pathology Informatics, Detroit, MI.

E-mail: mtuthil1@hfhs.org

Content

Immunoperoxidase staining of tissues has become an important routine aspect of pathology practice resulting in the development of automation technology to perform these assays. As orders are typically created in the Anatomic Pathology LIS, it is a logical next step to interface such orders to the instrument platform eliminating dual order entry and errors, improving efficiency, and thereby increasing capacity.

Technology

Sunquest CoPathPlus (Sunquest Information Systems, Tuscon, AZ), Dako Automatic Immunohistochemistry Stainer with DakoLink interface server (Denmark)

Design

A bidirectional HL 7 interface was implemented between Sunquest CoPathPlus version 4.1 (SQCP) and a Dako Automated Immunostain Platform allowing immunohistochemistry orders place in CoPath to be received in the DakoLink instrument control software markedly simplifying run setup. Slides are required to be labeled with vendor proprietary asset tags.

Results

While slides still need to be manually labeled for runs, the elimination of dual order entry by automation of order entry markedly decreases assay run time saving upward of 360 hour of manual effort per year, eliminating errors, and improving laboratory throughput.

Conclusions

Implementation of an interface between the AP LIS and automated staining platforms save times and eliminates errors increasing laboratory capacity and throughput as well improving patient safety.

The First Conversion of Pathology Assets to/from an APLIS - Lessons Learned

Lyman T. Garniss, James Floyd, Ling-Ling

Massachusetts General Hospital, Department: Pathology Informatics, Boston, MA.

E-mail: lgarniss@partners.org

Content

Massachusetts General Hospital (MGH) Pathology Service recently implemented Sunquest's CoPath Plus version 5.0 This was not the first implementation of Sunquest CoPath Plus v 5.0 but it was the first time that large numbers of unique cassettes and slides were converted from a foreign system into CoPath Plus (or any APLIS) and could be recognized and processed in the new APLIS.

During the implementation a team of dedicated specialists from Sunquest, Massachusetts General Hospital and Partners Healthcare Systems Information Systems converted over 20 years of Anatomic Pathology data. This included over 2.4 million cases, 1.8 million unique tissue cassette numbers and 4.2 million unique slides numbers.

Technology

The technology to accomplish this project included; The existing PowerPath APLIS database with unique asset identifiers for specimen cassettes and slides; programs and formatting rules supplied by Sunquest, several programs, filters and conversion utilities developed at Partners Healthcare Systems Information Systems and the receiving CoPath Plus v 5.0 database.

Design

Sunquest's CoPath Plus version 5.0 has the ability to accept, store and make available "foreign identifiers". In the case of the MGH data conversion the PowerPath native identifiers for cassettes and slides were moved to the foreign identifier fields in the case records of CoPath.

Results

A newly installed APLIS (CoPath Plus) was able to open, access and process new tests and orders on cassettes and slides from a foreign APLIS for the first time. The process was not easy and many lessons were learned while converting the assets and cases.

Conclusion

This was the first time that a new APLIS was used convert, store, access and order new tests on cassettes and slides from a foreign APLIS. The "converted" assets can be used to order new stains, new slides, order whole slide imaging, and order molecular tests years after the case has been finalized. Slides and cassettes can also be more easily tracked and retrieved.


   Electronic Poster Session Top


Session-1-2

Wednesday-Thursday, October 5-6, 2011 (1:00 - 1:25 pm)

Grand Ballroom Foyer

Validation of a Transfusion Medicine Clinical Decision Assistance Algorithm

Riley Alexander, John H. Lunetta, Steven F. Gregruek

Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, IN.

E-mail: realexan@iupiu.edu

Content

Patient safety and cost-containment concerns have increased scrutiny of the medical appropriateness of blood component transfusion orders. Review of transfusing physician compliance with institutional guidelines is mandatory. Clinical decision assistance models provide an increasingly desirable method to aid proper blood utilization. We built a decision-tree algorithm constructed from our institution's approved transfusion guidelines to aid clinicians and reviewing pathologists in decision-making. Our ultimate goal is to incorporate it into the laboratory information system (LIS) and electronic ordering system for daily usage.

Design

We constructed a decision tree-based model in Adobe Captivate (San Jose, CA) which allows the physician to select the requested blood component (e.g. packed red blood cells, plasma, etc.), then leads the user through a series of decision points utilizing the patient's clinical and laboratory information, ending with an administration recommendation. Decision points and recommendations were drawn from approved institutional transfusion guidelines.

Technology

The algorithm was constructed for the purposes of validation completely within Adobe Captivate 5 (San Jose, CA) using a decision-tree framework.

Results

Expected navigation through the model for each blood component and for each clinical/laboratory decision point was observed. Appropriate transfusion recommendation for all possible pathways through the algorithm was verified, and the model performed as expected.

Conclusion

An institution's transfusion guidelines can be effectively built into a decision tree algorithm to allow targeted and effective clinical decision assistance. In its current form, the model may be utilized as a teaching tool. Optimally, it will be embedded within the LIS and electronic ordering system to ensure blood component ordering and review follows a systematic, evidence-based method that adheres to institutional guidelines. It may also be translated from the test platform, Captivate, to a device agnostic web-based or smartphone module to provide ready access for clinicians, medical students and pathologists.

A Clinically Integrated Database to Expedite Translational Research for the Specialized Program of Research Excellence in Head and Neck Neoplasm Project: An Update

Waqas Amin, Harpreet Singh, Ann Marie Egloff, Jennifer Hetrick, Althea M. Schneider, Brenda Diergaarde, Jennifer Grandis, Anil V. Parwani

University of Pittsburgh School of Medicine, Pittsburgh, PA.

E-mail: aminw@upmc.edu

Background

The specialized program of research excellence (SPORE) in Head and Neck Neoplasm Database is a bioinformatics supported system incorporating demographics clinical, pathological, and molecular data into a single architecture carried out by a set of common data elements (CDEs) in order to expedite head and neck cancer research. The database is built to provide semantic and syntactic interoperability of data sets and to make the data flexible, shareable and understandable across multiple systems, and end-users.

Technology

The database provides a web-based data annotation and query tool that is supported in a three-tiered architecture and is implemented on an Oracle Application Server v10.1.2.3 running on a Windows 2003 and Oracle RDBMS v.10.2.0.2 running on an AIX 5L virtual host definition supported by IBM x3850 system hardware. The application utilizes the Oracle http server and mod_plsql extensions to generate dynamic web pages from the database to the users.

Design

The various components of the annotation and query tool include:

  1. Common Data Elements: CDEs are developed using the College of American Pathologists (CAP) Checklist and North American Association of Central Cancer Registries (NAACR) standards,
  2. Data Annotation Tool: This is a portable and flexible Oracle-based data entry device and an easily mastered, web-based tool.
  3. Data Query Tool: This tool facilitates the search of de-identified within the data warehouse through a "point and click" interface, thus enabling only the selected data elements to be essentially copied into a data mart using a dimensional-modeled structure from the warehouse's relational structure.
Results

The SPORE Head and Neck Neoplasm Database contain multimodal datasets that are accessible to investigators via an easy to use query tool. The database currently holds 7662 cases and provides demographic, clinical, pathology, treatment, follow-up, patient and tumor genomic and other molecular data to 12281 tumor accessions.

Conclusion

The SPORE Head and Neck Neoplasm Database provides an informatics support to facilitate basic, clinical and translational science research. It offers a mechanism to efficiently identify and get access to well annotated biospecimens to meet their research interests and requirements with the goal of integrating laboratory data from multiple investigators in order to develop a comprehensive characterization of individual patients and tumors. The tool protects patient privacy by providing only de-identified data with Institutional Review Board and scientific committee review and approval.

National Mesothelioma Virtual Bank Expansion: A Clinically Annotated Tissue Resource to Expedite Translational Research

Waqas Amin 1 , Michael Baldonieri 1 , Michael J. Becich 1 , John Milnes 1 , Anil V. Parwani 1 , Althea Schmeider 1 , Nancy Whelan 1 , Sharon Winters 2

1
University of Pittsburgh School of Medicine, Pittsburgh, PA, 2 University of Pittsburgh Medical Center, Pittsburgh, PA.

E-mail: aminw@upmc.edu

Background

The National Mesothelioma Virtual Bank (NMVB), developed five years ago, gathers clinically annotated datasets relevant to human mesothelioma research. During this period of time, this novel resource has greatly increased its collection of specimens and provided hundreds of tissue samples and data sets to investigators. By including new collaborating sites and marketing the resource to a larger research community, the NMVB hopes to increase the rate of collection of samples over the next five years.

Design

The NMVB architecture consists of three major components: (a) common data elements (based on CAP protocol and NAACCR standards), (b) clinical and epidemiologic data annotation, and (c) data query tools. Over the last five years, the NMVB collaborating sites have consisted of New York University, University of Pennsylvania and University of Pittsburgh Medical Center. The newest collaborating site, Mount Sinai School of Medicine, has joined as collaborator for the next five year to increase the collection of specimens, allowing the resource to evolve and adapt to the needs of both the clinical and scientific research communities. In addition to marketing efforts at both national and international conferences to expand the awareness and expand availability of the tissue and data bank, two new Tissue Microarrays (TMAs) have been created and made available for a broader research this year.

Result

The database provides researchers real-time, interactive access to richly annotated specimens database and integral information related to mesotheliomas. The data disclosure and specimen distribution protocols are tightly regulated to maintain compliance with participating institutions' IRB and regulatory committee reviews. The NMVB currently has over 950 annotated cases available for researchers, including paraffin embedded tissues, fresh frozen tissue, tissue microarrays, blood samples and genomic DNA.

Conclusion

The National Mesothelioma Virtual Bank (NMVB) is a virtual biospecimen registry with robust translational biomedical informatics support to facilitate basic science, clinical, and translational research. Furthermore, it protects patient privacy by disclosing only de-identified data, making biospecimens readily and efficiently accessible to researchers free of charge.

A Model for Utilizing

Automated Image Analysis Software for Phase 1 Biomarker Studies


Tanner L. Bartholow, Michael J Becich, Anil V. Parwani

University of Pittsburgh School of Medicine, Pittsburgh, PA.

E-mail: bartholow.tanner@medstudent.pitt.edu

Content

Tissue microarrays provide a means to study novel immunohistochemical biomarkers for cancer diagnosis and prognosis in Phase 1 biomarker studies. With cores from numerous cases included on the same microscope slide, each case can be immunostained under the same conditions, utilizing less reagents and ensuring standardization. Subsequent staining quantification, however, has traditionally been performed manually, although such a determination may be subjective, with suboptimal interoperator agreement. The use of automated image analysis algorithms may aid in standardizing the results.

Technology

Utilizing digital whole slide imaging and automated image analysis software, it is possible for the software operator to preselect the parameters for assessing the staining intensity across each tissue core in a standardized manner. Such technology has the provisions to allow the user to select the range for staining intensity and features algorithms to allow the staining to be quantified by pixel count, nuclear staining, or membranous staining, enabling biomarkers located in different cellular locations to be studied.

Design

Previously we have constructed tissue microarrays consisting of specimens of normal donor prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, normal tissue adjacent to prostatic adenocarcinoma, primary prostatic adenocarcinoma, and metastatic prostatic adenocarcinoma and stained them for ezrin-radixin-moesin-binding phosphoprotein 50 and Slit2, both potential biomarkers for prostate cancer. The tissue microarrays were scanned as digital whole slide images and analyzed utilizing an automated image analysis software pixel count algorithm, with the different groups subsequently compared.

Results

In the ezrin-radixin-moesin-binding phosphoprotein 50 stained specimens, among the other differences noted, metastatic prostatic adenocarcinoma stained significantly less than primary prostatic adenocarcinoma (p=0.006). In the Slit2 stained specimens, among the other differences noted, primary prostatic adenocarcinoma stained significantly less than normal donor prostate (p<0.05).

Conclusions

Utilizing the automated image analysis software, we have been able to identify both a potential prognostic biomarker and a potential diagnostic biomarker for prostate cancer. Automated image analysis software has the potential to be applied in Phase 1 biomarkers studies to assess differential tissue expression patterns for clinical research.

An Innovative and Agnostic Digital Pathology Solution, Utilizing Cutting-Edge Technology, to Increase Production and Overall Advancement of Translational Research

Dave Billiter 1 , Thomas Barr 1 , Kathleen Nicol 1 , Patrick Samona 2 , William Hinchman 2 , Jordan Savage 2

1
The Research Institute at Nationwide Children's Hospital, Columbus, OH, 2 Vectorform, LLC, Brooklyn, NY.

E-mail: dave.billiter@nationwidechildrens.org

Content

The Research Informatics Core and the Biomedical Imaging Team at The Research Institute at Nationwide Children's Hospital, in collaboration with Vectorform LLC, is committed to advancing the field of digital pathology by increasing performance of the technology and supporting an 'agnostic approach to support the pathology discipline and translational research. With the emergence of multiple vendors and accompanying solutions (robots and software), the need for an advanced solution integrator to leverage the advantages of all solutions was apparent.

Technology

The Image Viewer utilizes Microsoft. NET and Silverlight for display in Microsoft Deep Zoom Image format. The annotations utilize a Windows Communication Foundation (WCF) service in relation to the Image Viewer and the Annotations database (SQL Server). The Image Analysis suite utilizes algorithms written in C# with Image Magic wrappers. Microsoft's Kinect is a motion sensing input device featuring an RGB camera, depth sensor and multi-array microphone.

Design

The design is modular in nature, with a service-oriented structure, to enable integration and interoperability.

Results

The Digital Pathology solution will utilize multiple Microsoft products including HealthVault, Azure Cloud, Deep Zoom and Windows Presentation Foundation, as well as, open-source tooling to complete the informatics plumbing. This innovative solution creates an inspired user experience for viewing high fidelity imagery and patient models. Pathologists and researchers can utilize the various input methods provided to quickly navigate through the case load and create visual and audio annotations. The digital pathology system will also support remote collaboration between physicians and include real-time annotation.

Conclusion

The innovative solution will facilitate standardization in the field, while also advancing telemedicine, computer-assisted decision support, pattern recognition, integration of disparate sources and advancing the overall workflow to support the scientific community. The harmonization of innovation in technology and practice aims to revolutionize the art of pathology while enhancing scientific output.

Predicting Lymph Node Metastasis Status Via Image Analysis of Primary Breast Tumor Histology

David E. Breen 1 , Alimoor Reza 1 , Bian Hu 2 , Aladin Milutinovic 2 , Fernando U. Garcia 2 , Robi Polikar 3

1
Drexel University, Philadelphia, PA, 2 Drexel University College of Medicine, Philadelphia, PA, 3 Rowan University, Glassboro, New Jersey.

E-mail: david@cs.drexel.edu

Content

Despite a variety of new tumor markers resulting from significant progress in the molecular and genetic characterization of breast malignancies, axillary lymph node metastasis status remains one of the most critical prognostic variables for the breast cancer management decision-making process and patient survival. Surgical methods for determining metastasis status of breast carcinoma need improvement because they may lead to unnecessary surgeries and its complications. The objective of our study is to demonstrate that lymph node metastasis status may be predicted via computerized image analysis of primary breast tumor histology.

Technology

A complete computational pipeline that includes image processing, shape/color analysis and machine learning algorithms has been developed to perform automated metastasis status prediction. The stages in the pipeline include: 1) selection and scanning of stained histology slides, 2) automated segmentation of cancer cells and tumor structures, 3) computing geometric measures from stochastic geometry that transform cancer cell/tumor shapes into shape distributions, 4) creating intensity distributions from the texture variation / nuclear hyperchromasia levels within cancer cells, 5) mapping the high-D shape/color distributions into a lower dimensional feature vector, and 6) stacked Relevance Vector Machines (RVMs) that classify test samples into lymph node metastasis status.

Design

Pathologist-selected subsections of 100 primary breast carcinoma specimens, stained with a complete prognostic panel, were scanned at a resolution of 6000×6000 pixels. The computational pipeline processed the scanned specimens, producing a metastasis status prediction for each specimen (N0 - no metastasis, N1 - metastasis to axillary lymph nodes).

Results

Computational results were generated from the 100 carcinoma specimens with known metastasis status. Using Leave-One-Out validation the stacked RVM classifiers were able to correctly classify the metastasis status of 90 specimens. The classification results have a specificity of 100% (all 53 N0 samples correctly classified) and a sensitivity of 79% (37 of 47 N1 samples correctly classified). Thus producing a positive predictive value of 100% and a negative predictive value of 84%. The area under the associated ROC curve is 0.842.

Conclusion

Our computational image analysis of histology of the primary tumor can predict lymph node metastasis and shows promise as an effective means to determine the absence of nodal metastasis.

Development of a Web-based Digital Pathology Consultation Portal (DPCP) for Providing Second Opinion Consultation Services

William Cable, Samuel A. Yousem, Jeffrey McHugh, Andrew Lesniak, Eugene Tseytlin, Jon Duboy, Ishtiaque Ahmed, Gary Burdelski, Denine Maglicco, Gonzalo Romero Lauro, Liron Pantanowitz, Anil V. Parwani, George K. Michalopoulos

University of Pittsburgh Medical Center, Pittsburgh, PA.

E-mail: cablew@upmc.edu

Background

Our institute has developed a web-based tool for receiving and processing digital pathology consultation requests. The tool allows for the viewing of whole slide images stored at a laboratory in China by pathologists at their computers in Pittsburgh.

Technology

The remote facility is using the Hamamatsu NanoZoomer 2.0-HT scanner to capture whole slide images. They are using the Zebra GX430t barcode printer with NiceLabel application to ensure slides are correctly associated with requests. Our team built the web application in ColdFusion 9.0 with a SQL Server database. The slide viewer is an internally-developed Java applet, supporting multiple vendor WSI formats with annotation capabilities. The system utilizes a webservice architecture to integrate with the vendor slide archive. Data exchange is via XML. Pathologists in Pittsburgh will be able to view the whole slide images in China, using streaming technology to avoid transferring large data sets across the network Figures.

Design

The web tool features the following:

Client submission and request tracking

Offers SSL (https) secure login for client personnel to submit patient data, print slide labels, view the current status, and view and print second opinion reports.

Host Pathologist

Hosts the diagnosis tool where pathologists can view whole slide images, annotate and capture image snapshots, view clinical data, and submit diagnosis for second opinion reports.

Host Consultation Services

Allows managers to triage requests, assign them to pathologists, monitor workflow, and maintain personnel data.

Host Transcriptionist

Lists current transcription queue with data entry fields for diagnoses dictated by pathologists through current Dicataphone system.

Goals

The web tool will go live September 21, 2011. In the first year we anticipate completing 2000 consultations, to grow to 10,000 within three years. Turn-around-time will be within 72 hours of submission.



Conclusion

The digital telepathology solution allows patients in China to quickly access the expertise of our institute pathologists for second opinion consultations. Our institute and client institute have collaborated to overcome the significant challenges inherent in telepathology across vast distances, making this approach feasible for other telepathology opportunities.

Lessons Learned: Logistics and Utility of Prospective Whole Slide Digital Image Scanning of Clinical Cases

Sue Chang, Sergey Mareninov, Tracie N. Pham, Aaron Wagner, Juan Sebastian, Dennis Sunseri, Clara E. Magyar, Sarah Dry, William H. Yong

UCLA Medical Center, Department of Pathology and Laboratory Medicine, Los Angeles, CA.

E-mail: suechang@mednet.ucla.edu

Content

At UCLA, the Division of Neuropathology has been generating whole slide digital images (WSDI) of clinical brain tumor cases prospectively since 2008. This study discusses our protocols, the benefits and limitations, and future directions.

Technology

Scanner: Aperio ScanScope XT (Vista, CA). Database: Aperio Spectrum, currently using 5.5 tetrabytes. Daily incremental backups to a Dell MD3000 SAN, 8.8 tetrabytes of space, behind a firewall. Monthly and yearly backup to LTO4 tapes using Dell TL4000 tape library and Symantec Backup Exec software, stored off-site. Retrieval: Aperio ImageScope on institutional computers, or any browser using UCLA virtual private network. Total storage volume occupied: 3 tetrabytes per year, with 5% growth per year.

Design

Pathologists select the best representative slides (H&E, immunostains) for scanning, and the technical staff transports slides to the WSDI scanner. Priority is given to slides for the weekly brain tumor board. WDSIs are scanned at Aperio 20X magnification unless otherwise requested. A neuropathology technician labels each WDSI and organizes them into folders by patient name and surgical number, using the scanner's image management software (Spectrum).

Results

We have established a workflow and protocol for prospective scanning, and have archived ~9000 WDSIs representing >1200 cases, currently at an average of 8 cases per week. Besides providing an archive for glass slides, including returned outside consultation slides, the highest activity use is for weekly tumor board meetings. Other uses include identifying best blocks for research or clinical testing, quick reference of original slides at time of tumor recurrence, and image analysis for research.

Conclusion

The database contains only select representative slides, as scanning all slides is inefficient for uploading, storage, and retrieval. Lowering costs for data storage and back-up is essential to permit larger scale scanning. Integration of the pathology information system and Aperio software would alleviate the current largely manual labeling of WSDIs. Scanning at Aperio 20X suffices for our purposes, but does not for some detailed histologic studies. While we have local back-up to a second server, we use tapes for remote back-up. Automated remote back-up is desirable but requires greater bandwidth and infrastructure than we have. Given that brain tumor cases are a minute subset of a Pathology Department's slide output, substantial challenges remain for department-wide prospective imaging of clinical cases.

Dynamic Non-Robotic Telemicroscopy Via Skype: A Cost-Effective Solution to Teleconsultation

Adela Cimic 1 , S. Joseph Sirintrapun 2

1 University of Sarajevo Clinical Center, Sarajevo, Bosnia, 2 Wake Forest University, Baptist Medical Center, Winston Salem, NC.

E-mail: jsirintr@wfubmc.edu

Content

Skype is a peer to peer software application that has been historically used for voice and video calls, instant messaging, and file transfer over the Internet. Skype has a screen sharing option; making it an economical means of videoconferencing. Few studies are available using Skype specifically for telepathology. Our aim is to show that without expensive robotic equipment or digital slide scanners, dynamic non-robotic teleconsultation is possible and even effective via means of a standard microscope camera capable of live acquisition, Skype, an established broad band internet connection, and experienced pathologists.

Technology

Versions of Skype used in this study are Skype 5.0 and above. Only well-established broadband internet connections are used, usually between academic medical institutions. Connections from local "hotspots" were avoided where internet connections are potentially tenuous. When transmissions were international, internet transmission speeds ranged from 1.0 Mb to 2.0 Mb. When domestic, transmission speeds were faster ranging up to 5.0 Mb. When over the same institutional network, speeds were even faster ranging from 33 Mb to 100 Mb.

A SPOT Insight Wide-field 4 Mp CCD Scientific Color Digital Camera is used for capturing images. Live images are displayed using the SPOT Advanced Software. Through the Skype Screen Share option, the receiving "consultant" pathologist is able to view the sending "consulting" pathologist's screen with the images live captured in the SPOT Advanced Software. Communication between pathologists is easily performed via computer microphones, headsets, and/or speakers through Skype.

Design

Both the consulting "sending" pathologist and consultant "receiving" pathologist are reasonably experienced general surgical pathologists at junior attending level with several years of experience in signout. Forty-five cases encompassing a broad range of surgical pathology specimens were selected including some hematopathology and neuropathology cases. The cases were prospectively evaluated with the consultant diagnosis used as a preliminary pathologic impression with the final diagnosis being confirmation after the case has been thoroughly worked up.

Results

Thirty of forty-five cases (2/3) cases had the consulting impression match exactly the final diagnosis. In an additional eleven cases, the consulting impression gave a differential but favored a diagnosis which after workup, became the final diagnosis. This essentially makes forty-one of forty-five cases (91%) concordant. In three cases, the consulting impression gave a differential, but favored an entity which did not match the final diagnosis. However, the morphologic differential of the consulting impression was phrased in such a generic means that there was not a discrepancy. Only one case (2%) did the consulting impression not match the final diagnosis; a disconcordant opinion.

Conclusion

The image quality via Skype screen sharing option and using the SPOT Insight Camera is excellent. When considering using Skype for teleconsultation, image quality is limited only by what is captured by the image acquiring device. Essentially no lag time was seen. We have shown in our small pilot study that Skype is an effective cost-efficient means for teleconsultation, particularly in the setting of entity-related differential diagnoses in surgical pathology and when both the consulting and consultant pathologists are reasonably experienced.

Back to the Future: Analog Again? An Analog Computer Model of Platelet Transfusion

Steven F. Gregurek 1 , Julie L. Cruz 2

1
Indiana University School of Medicine, Indianapolis, IN, 2 Indiana Blood Center, Indianapolis, IN.

E-mail: steven.gregurek@gmail.com

Content

While digital modeling of physiologic responses and processes has proven utile for both education and decision-support, they may have limited credibility as they are unconstrained by limitations impacting the system they purport to represent. In the case of the impact of platelet transfusion on a patient's platelet concentration, we investigated the application of an analog computer whose system represents analogous constraints.

Technology

An analog computer (Plateletron Prototype Instrument, Advanced Design and Instrumentation, Indianapolis, Indiana) was chosen, since the behavior of a resistor-capacitor (RC) circuit closely mimics the physiologic behavior of platelet concentration - where capacitance mimics blood volume and voltage mimics platelet concentration.

Design

In the resistor-capacitor circuit of the Plateletron an increase of 100 millivolts corresponds to a platelet concentration increase of 10k/dL. The analog user interface allows consideration of variables related to platelet production, sequestration and consumption. Dials allow the user to select the patient's thrombopoeitic potential (reflecting bone marrow status) and level of thrombopoeitic stimulus (thrombopoetin, etc.) with the combined effect on platelet production indicated on an analog meter. Additional dials allow input of the level of splenic sequestration (asplenia, splenomegaly) as well as application of pathologic consumptive processes (HIT, TTP, DIC, refractory, etc). Large bleeding events (fast vs. slow) are applied via switch, and indicators illuminate when bleeding stops. Plateletspheresis transfusions (up to six) are applied via switch with indicator. A real time platelet count digital indicator provides data on the impact of the above variables and the resultant platelet count response to the simulated transfusions. The device operates on 40 volts DC.

Results

The Plateletron model successfully predicted expected post-transfusion response for mock patients including normal control, massively bleeding, highly refractory and HIT patients. Validation of additional pathologic processes is underway.

Conclusion

Platelets are often over transfused and decisions regarding dosing and indications are often complicated and difficult. The Plateletron instrument should prove an effective simulation device to aid in the clinical decision making of platelet transfusion. Further, preliminary testing appears to support the use of a resistor-capacitor circuit model for platelet transfusion under a variety of conditions.

The Use of K-Nearest Neighbor Algorithm in the Classification of Peripheral Nerve Sheath Tumors

James R. Hackney, Jonas S. Almeida

University of Alabama at Birmingham, Birmingham, AL.

E-mail: jhackney@uab.edu

Content

Histopathological diagnosis remains a difficult task to automate. Attempts to identify predictive explicit models have been successful as far as identifying specific structural components such as cell boundaries and intracellular components, but remain challenging when the target features are less geometrically defined, such as tissue organization. As a result, the subtleties of histopathologic diagnosis usually require the intervention of a domain expert to perform image segmentation and to establish areas of interest (AOIs) that are likely to be clinically useful. However, the resistance of implicit modeling to automation has been partially breached with advanced machine learning tools that seek to mimic experiential learning such as artificial neural nets, support vector machines, random forests, and Bayesian classifiers.

Technology

We report the use of a simple machine learning algorithm, the k-nearest neighbor classifier, for the prognostic classification of benign and malignant peripheral nerve sheath tumors, including tumors that were considered to be "gray zone" lesions of uncertain malignant potential by histopathology.

Design

Our implementation of the k-nearest neighbor algorithm involved comparing the color intensity of the red, green, and blue channels of each pixel to the distribution of the values of its k-nearest neighbors. Data from the analysis of six benign neurofibromas and four malignant peripheral nerve sheath tumors were compared with each other and with the data from the analysis of three nerve sheath tumors uncertain malignant potential.

Results

The k-nearest neighbor algorithm shows promise in helping to distinguish histologically similar tumors that have different prognostic profiles as determined by international diagnostic criteria and clinical follow-up. However, additional studies are needed in order to confirm this impression.

Conclusions

While specific histopathological diagnosis may elude automation for the foreseeable future, the use of data-driven computational methods may provide important additional information useful in distinguishing closely related neoplastic entities that are morphologically similar but prognostically unique.

The Divergence of the CoPathPlus Anatomic Pathology Laboratory Information System Vended by Cerner Corporation and Sunquest Information Systems

Mehrvash Haghighi 1 , J. Mark Tuthill 1 , Raymond Aller 2

1
Henry Ford Hospital, Detroit, MI, 2 Keck School of Medicine, University of Southern California, Los Angeles, CA.

E-mail: mhaghig1@hfhs.org

Content

Selecting the right Laboratory Information System for a laboratory is a complex and time-consuming process. This is further complicated by the existence of systems sharing the same name such as CoPathPlus. This system is vended by two different companies: Sunquest Information Systems and Cerner Corporation with rights to independently modify and to further develop the base-code. While earlier versions of CopathPlus are identical, the product began to diverge after CopathPlus 2.2. This abstract will describe the key differences between two systems through comparison of the application features, underlying core technology and future development, and product road maps.

Technology

We compared differences in the two systems by analyzing the current versions of CoPathPlus for differences between Sunquest v5.0, (SQCP) and Cerner v3.2, (CECP) in technology, development plans, application modules, user interfaces and each company's road map for future releases. Data was gathered from published materials by each company 1,2, LIS products guide in CAP Today online 3 and consulting the users of each system.

Results

Since the Cerner and Sunquest began to independently modify source code the two systems have diverged markedly. Most differences are in application features, such as difference in the user interface put in place in SQCP as well as application modules for data structuring. Other significant application differences include different approaches to tracking and routing modules, and digital pathology in both product offerings. Current versions while similar in terms of hardware platform requirements also show divergence: CECP is certified for Windows 7 and Vista, while SQCP is restricted to Windows XP. Version 5.0 SQCP will migrate to Sybase 15 allowing for a 64 bit OS as will CECP v3.2; SQCP will require a future to release to support MS SQL.

Conclusions

Anatomic pathology laboratory information system (AP-LIS) with the "same" name may have diverged in development which causes confusion for customers. Overall the two systems being child derivatives are very similar in "application features" with the main differences being the method of delivery. Although they have unique attributes, they render comparable efficiency and efficacy. Since application features change rapidly compared to core technology, selecting the best system for specific environment requires focus on the characteristics of the core technology rather than the individual features.

References

  1. Cerner.com support users. https://cernercare.com
  2. Sunquest iMentor. http://imentor.sunquestinfo.com/sqclient
  3. Anatomic pathology guide. (2011).Retrieved July, 2011, from http://www.captodayonline.com/productguides
Whole Slide Imaging (WSI) for Cervical Cytology Proficiency Testing: A Feasibility Study

Nicholas C. Jones, Brenda J. Sweeney, David C. Wilbur

Massachusetts General Hospital and Harvard Medical School, Boston, MA.

E-mail: ncjones@partners.org

Content

Whole slide imaging (WSI) could serve as a replacement for CLIA-mandated cervical cytology proficiency testing (PT). Currently PT requires the costly and laborious collection and maintenance of large glass slide sets. WSI could obviate this need and would substantially streamline the testing process and administration. This study tests the feasibility of WSI use for this task.

Technology

WSI on cervical cytology specimens for PT.

Design

Ten previously interpreted SurePath TM cervical cytology specimens were scanned using the Zeiss Mirax Midi scanner. Slides selection was based on a typical mix of cases for CLIA glass slide PT. Eight cytologists received a short training program for the Mirax Viewing station and then reviewed the slides for up to two hours and provided diagnoses in the CLIA PT format. Test takers were asked to comment on the technology and issues which were noted during the testing process.

Results

Six of the eight cytologists received scores of 100 (passing is 90 or above). Two cytologists failed the challenge with scores of 80 and 85. One failed by interpreting a slide with a high grade lesion as negative, while the other failed by making multiple over interpretations. Critical comments made by the test takers included problems with slide navigation, the size of the field of view (too large), lack of focusing capability for 3-dimensional group visualization, and the brightness of the screen (too bright). Positive comments included an overall general enthusiasm for the concept.

Conclusion

This study was limited by a number of factors, including a low sample set of test takers, a minimal amount of training and experience using WSI, lack of validated slides (90% pre agreement on the diagnosis), limitations due to lack of user customization of screen brightness and size, and single plane scanning resulting in lack of focusing capability. Despite these issues the majority of the cytologists were able to achieve passing scores, leading to the conclusion that with further refinement of slide set and operational parameters, and with increased training and experience with WSI, this system may be a viable alternative to the current glass slide-based PT program.

Natural Language Processing for the Development of Structured Hematopathology Reports

Veronica E. Klepeis, John R. Sharko, Kevin S. Hughes, Aliyah R. Sohani, Thomas M. Gudewicz

Massachusetts General Hospital, Boston, MA.

E-mail: vklepeis@partners.org

Content

Traditionally, pathology reports are written in free text, which leads to a high degree of variability. This is especially true for hematopathology diagnoses, which often include detailed notes. Retrospective analysis of surgical pathology reports can be used to build a specialty-specific structured dictionary of terms. Natural language processing (NLP) can be used to extract information towards this goal.

Technology

NLP software developed by Clear Forest Corporation (Waltham, MA) was used to extract words and word sets from hematopathology reports signed out at Massachusetts General Hospital (Boston, MA).

Design

Hematopathology surgical pathology reports signed out over the past seven years were retrieved (15,407) and the "top line" diagnosis was extracted. A subset of reports (8,821) was input into Clear Forest, which generated a list of entities (i.e., words and word sets). Entities that pertained to pathologic diagnoses were used to formulate patterns and generate an extraction module that would assign reports to specific disease categories based on the "top line" diagnosis. The module was then applied to the complete cohort. Microsoft Office Access was used to analyze results.

Results

Clear Forest recognized 11,512 entities, 74% of which were considered not useful in formulating patterns to capture the multiple ways of wording a specific diagnosis. Patterns for mature B-, T- and NK-cell neoplasms were simpler compared to myeloid neoplasms, as the latter diagnoses are more varied in structure and content. Benign diagnoses also required lengthy patterns to include all possible combinations of terms. This is reflected in the number of entities recognized by the patterns in each disease category (Table 1). Upon applying the extraction module to the complete cohort of reports, only 698 new entities were encountered, of which 82% (573/698) were considered not useful. Of the 125 useful new entities, 33% involved typographical errors and 34% were related to non-hematologic diagnoses. This translated into only 329 of 15,407 reports (2.1%) being unassigned to a disease category.



Conclusion

NLP is useful for analyzing free text reports to develop a comprehensive dictionary of diagnostic terms. Structured data reports will simplify assignment of billing codes and mining of data for research.

Computer Assisted Interpretative Reporting of Special Coagulation Test Results

William J. Lane, Vinay S. Mahajan, Robert I. Handin

Brigham and Women's Hospital, Boston, MA.

E-mail: wlane@partners.org

Content

Many special coagulation labs write customized interpretive reports to help clinicians understand the results from this complex area of testing. We converted our partially paper-based and completely manual interpretive reporting process to an all electronic process with customized software to assist and optimize the workflow.

Technology

We wrote a custom interpretive reporting program in Python (ActiveState Software, Vancouver, BC, Canada). Special coagulation lab data is obtained using an automated LIS data dump and molecular coagulation factor results are batch downloaded from PowerPath (Elekta AB, Stockholm, Sweden). The data is merged and stored in a SQLite database.

Design

Interpretation reports range from needing little customization to those that require advanced level coagulation knowledge and an understanding of the patients' clinical history. Nevertheless, all interpretive reports start as automatically created canned statements based on the patient results. Each time the program runs it self-validates its functionality. The program interface displays a series of steps that the resident must perform. Training is done by the previous resident in combination with instructions on our internal wiki.

Results

Over the last year, the program has been used to write 90-100 interpretive reports per week. Technologists no longer fill out paper result sheets. Residents no longer sort paper result sheets, look up corresponding molecular tests, manually cut and paste the interpretation reports together, or manually type the sample and patient identifiers. Our system also automatically creates a properly coded billing sheet, a process previously done manually. In addition to the time savings, the above changes almost certainly cut down on errors arising from repeated manual data entry and misplaced paper result sheets. However, most importantly it allows the residents to focus on looking up clinical histories, resulting in improved personalization and quality of the interpretive reports.

Conclusions

By creating a custom interpretive software platform and streamlining the workflow we were able to increase efficiency, reliability, and create better interpretive reports. We hope that by detailing our approach and releasing our dictionary of interpretive text blurbs that others would be able to do the same. In addition, our system could be extended to use other types of laboratory data.

CytometryML Data List with Relationships

Robert C. Leif, Stephanie H. Leif

Newport Instruments, San Diego, CA.

E-mail: rleif@rleif.com

Content

The Web Access to DICOM Persistent Objects, WADO, approach to the interfacing of DICOM with the Internet uses XML equivalents of standard DICOM database commands. Although the use of these commands is necessary, in many cases, the use of standard hypertext commands would be more user-friendly. The International Society for Advancement of Cytometry, ISAC, is developing a table of contents, ToC, approach to describe the contents of zip files that are similar to DICOM series and instance files. CytometryML, Cytometry Markup Language, includes a ToC that is based on the DICOM model and includes the equivalent of Resource Description Framework relationships that include hypertext linkages and extends and refines the ISAC ToC.

Technology

XML schemas were validated against the XML Schema Definition Language (XSD) and translated into XML.

Design

CytometryML consists of 4 major XML schemas: Series, Instance, Instrument, and Specimen; it also includes Image and List-Mode schemas. Series metadata that is specific for an entire collection of images and/or list-mode files produced by a single instrument and derived from a single specimen is stored together with associated metadata files in a container (ZIP) file. Each Instance container file includes binary image and/or list-mode files together with associated metadata files that are specific for a single or closely related group of instrument runs from a single specimen.

Results

The ISAC Archival Cytometry Standard (ACS) proposed ToC schema including its Resource Description Framework (RDF) capabilities has been extended and modified for use in the Instance schema. This design has been tested with flow cytometry files and image files are presently being integrated. The binary data containing files have been organized into a hypertext driven linked list. The replacement of standard RDF syntax by a simple sentence based format (Subject, Predicate, and Object) permits multiple relationships between two file references.

Conclusions

The capacity to merge components of two standards, DICOM and ACS, has been demonstrated. The organization of the data into hyperlinks that are augmented by relationship descriptions, will permit the development of simple, effective user interfaces. The optimum means of presentation would be the combination of HTML and XML.

Mobile "App" Overload. The Prospect of Medically Useful Web-Based Content Utilizing Mobile Device/Platform Agnostic Standards

John Lunetta 1 , Riley Alexander 1 , Steven Gregurek 1 , Tony Island 2

1
Indiana University School of Medicine, Indianapolis, IN, 2 Indiana Blood Center, Indianapolis, IN.

E-mail: jlunetta@gmail.com

Content

Increasing pressures driving evidence-based practice have incentivized electronic decision support tools and medical content delivery systems. Health care providers have adopted portable devices to augment the aging model of fixed workstations. Currently, most portables use device-specific native applications (apps). However, technology-assisted medical decision-making is desirable from web applications that are device/platform agnostic. The "mobile-web framework" refers to a new standard of Internet usage through current smart-phones or tablets connected to a wireless network. The World Wide Web Consortium (W3C) has published this new standard to promote a device-independent web, based on an open source framework that offers broad distribution and a scalable architecture. Therefore, appropriate styling is delivered automatically to the various device/platforms without the need to download native applications (apps). We sought to gain a sense of which current online medical resources had embraced this technology.

Technology

UptoDate.com (Waltham, MA), PubMed.com (NCBI, USNLM, NIH), Skyscape.com (Marlborough, MA), eMedicine/Medscape.com (WebMD LLC., New York, NY), Epocrates.com (Epocrates, Inc. San Mateo, CA), PathologyOutlines.com (Bingham Farms, MI), Validator.w3.org/mobile (Version 1.4.2 World Wide Web Consortium), Yahoo.com (Sunnyvale, CA), Google.com (Mountain View, CA)



Design

Six medically useful web-based resources were checked in a validator: W3C mobileOK Checker v1.4.2 (World Wide Web Consortium, MIT, ERCIM, KEIO). Two popular websites (Google.com, Yahoo.com) were used as controls. Classified as follows:

Agnostic (>80%)

Partially Agnostic (40-80%)

Non-Agnostic (<40%)

Results

5/6 (83%) failed to validate. 1/6 (17%) achieved partial validation: eMedicine/Medscape.com (WebMD LLC., New York, NY). Controls validated appropriately. Figure illustrates our findings.

Conclusion

Current web-based content delivery systems and medical decision-support tools do not meet the new "mobile-web framework" standard. These findings suggest potential limitations in awareness and preparedness on behalf of this market. Future compliance in this arena will better support health care providers by allowing them the freedom to choose mobile devices based on personal preference; rather than be dictated by device-specific native applications, untimely software updates, limited distribution, and other errata.

Utilizing Steganographic Techniques to Embed Metadata in Gross Images in the Pathology Laboratory

Joy J. Mammen 1 , S. Dibose Raj 2 , Feminna Sheeba 2 , T. Robinson 2

1 Christian Medical College, Vellore, India, 2 Madras Christian College (Autonomous), Tambaram, Chennai, India.

E-mail: joymammen@cmcvellore.ac.in

Content

Gross specimen images account for a significant proportion of images dealt with in pathology. Images are usually managed in a file folder system; few laboratories have dedicated PACS system that may provide auditable data. The ability to provide evidence of authenticity of the image is a factor that is seldom discussed. Digital steganography is a discipline that deals with the science of concealment of information within electronic files. We describe a method to create and embed contextual metadata data within the image that will ensure the authenticity of the image.

Technology

MATLAB 2009b (MathWorks Inc, MA, USA); Java Netbeans 6.9 (Oracle Corporation, CA, USA)); MySQL 2008 R2 Oracle Corporation CA, USA)

Design

For the purpose of demonstration of the concept, we have used a generic web-camera (MS LifeCam VX-700) at a gross station to acquire the images. The photographic device should be able to adjust the resolution, size and frame rate while capturing the image. Image device related metadata and time stamps (automatically acquired), patient demographic data (sourced from the patient master) and relevant contextual data acquired from the laboratory information system or input manually are converted into a binary string and encrypted (input message). The encrypted data is then embedded in the pixels of the image using the concept of steganography, in which each bit of the string is written into the least significant bit of a pixel, so that every pixel carries one bit of the input binary string. After embedding the stego-image is stored in the database for future retrieval and use.

Results

The application designed and developed by our team, has the ability to capture an image from a camera interface, embed a specific input message within the image itself and store it in a database. The encrypted data can be retrieved and the metadata is displayed in a human readable form with no degradation of the image quality.

Conclusions

Ensuring the security of images in pathology is a significant issue. Digital steganography offers a method of ensuring authenticity of gross images in pathology.

Continuous Improvement Process for the CAP electronic Cancer Checklists

Jaleh Mirza, Samantha Spencer, Jeffery Karp, Gregory Gleason, Richard Moldwin

College of American Pathologists, Deerfield IL.

E-mail: jmirza@cap.org

Content

Since 2006, the College of American Pathologists (CAP) has been creating electronic cancer checklists (eCC) to represent the data elements in the CAP Cancer Protocols. Most major anatomic pathology software vendors have adopted the CAP eCC model for standardizing data capture.

The CAP eCC Team works closely with CAP's Pathology Electronic Reporting Committee (PERT) and the CAP Cancer Committee to ensure that the eCC data elements accurately reflect the evolving CAP Cancer Protocol content. Challenges in process management include: version control to handle changing data elements from the CAP Cancer Protocols and cancer registries, terminology mappings (e.g., SNOMED CT and ICD-O3), evolving XML formats, quality assurance (QA), issue management, and user support.

Technology

XML, XML Schema, XSLT, HTML, Apex (Chapel Hill, NC) SQL Audit 2008; Microsoft tools (Redmond, WA): C#, Visual Studio.NET 2008, Visual Basic for Applications, SQL Server 2008, SQL Server Management Studio, Access 2007.

Design

The eCC database uses SQL Server; SQL Server Management Studio supports database analysis and QA queries. Checklist content is entered into the eCC database using the eCC Template Editor. VS.NET code converts eCC database records into versioned XML checklist documents. XSLT transforms eCC XML into HTML. The eCC Project Tracker software handles issue management and QA.

Results

Vendors use the eCC XML files to implement data-entry forms per eCC standards. Vendors and end-users regularly submit design comments, bug reports, suggestions and requests to PERT for review (submissions). PERT meets weekly to address these issues; approved changes are implemented by the CAP eCC Team. QA issues are brought to PERT and/or Cancer Committee for discussion and resolution. In the past year, PERT has processed almost 300 submissions, in addition to the QA review performed by the CAP eCC Team.

Conclusion

A process of continuous improvement for the eCC is based upon regular technical and content QA reviews, as well as input from PERT, Cancer Committee, vendors, and end-users (pathologists, cancer registrars). This process results in continually-improved electronic checklists that remain synchronized with the clinical content developed by the CAP Cancer Committee.

Comparative Evaluation of Open-source Image Analysis Methods for Quantitation of Plasma Cells by CD138 Immunohistochemistry in

Bone Marrow Biopsies


Mehdi Nassiri, Riley Alexander, Jiehao Zhou, Joshua Bradish, Magdalena Czader

Indiana University School of Medicine, Indianapolis, IN.

E-mail: nassiri@hemepath.com

Content

Estimation of CD138 positive cells in bone marrow samples can be used to evaluate tumor burden of plasma cell neoplasms. It has been hypothesized that reproducible quantitation by "eyeballing" can be difficult to achieve. Dedicated image analyzers and whole slides scanners might help to alleviate this problem, but they are expensive, and often use propriety software and algorithms. To address this, we studied open source and freely available image analysis methods.

Technology

Images were analyzed using the freely available ImageJ (NIH, Bethesda, MD) software, using area under the curve RGB method for the red channel (AUC RGB), and the Immunomembrane and ImmunoRatio plugins (University of Tampere, Finland). In addition, we performed the same analysis using the Immunomembrane and ImmunoRatio web-app, in advanced mode.

Design

Immunohistochemistry-stained bone marrow biopsy slides for CD138 (DAB chromogen) were selected from 88 consecutive cases. Percentage of plasma cells/total bone marrow cells was scored by two experienced hematopathologists as well as two first year residents. As a comparison, an uncompressed JPEG image (1600x1200 pixels) was captured at 20x magnification using an Olympus DP20 camera (Olympus, Center Valley, NJ). These images were then uploaded into both the web-apps and into ImageJ. Results were collected and analyzed using Statistica software (Tulsa, OK).

Results

Human based scores whether novice or expert fared more closely to each other (Spearman r= 0.88-0.96, p<0.05) than software methods (r=0.67-0.86). Expert pathologists' scores had the highest concordance (r=0.96). Software based results were similar to each other (r=0.77-0.9). The order of concordance of software based methods to expert scores was: Immunoratio (r=0.83) Immunomembrane (r=0.77) and AUC RGB (r=0.67).

Conclusions

Selection of multiple regions and elimination of acellular areas are important to achieve accurate results in software based methods. Despite the nuclear-scoring protocol of the ImmunoRatio software, it performed quite well. Using a simple AUC RGB method did not reveal adequate correlation and required image manipulation and background correction to produce desirable results. For those concerned with quantitative image analysis, freely-available web-based software might provide an acceptable alternative to expensive stand-alone systems.

Construction and Deployment of a Comprehensive Hematopathology Virtual Teaching Set

Christine G. Roth 1 , Bryan J. Dangott 2 , Tom Harper 2 , Jon Duboy 2 , Fiona E. Craig 1 , Anil Parwani 2

Department of Pathology, Divisions of Hematopathology 1 and Informatics 2 , University of Pittsburgh School of Medicine, Pittsburgh, PA.

E-mail: garciac@upmc.edu

Content

The practice of hematopathology is complex and requires a multiparametric approach, as hematopoietic neoplasms are currently classified into distinct clinicopathologic categories based on integration of the clinical, morphologic, immunophenotypic, cytogenetic, and molecular findings. Comprehensive teaching sets, with inclusion of whole slide images (WSI) can help adequately prepare trainees to practice in the current era.

Technology

Whole slide scanner: Aperio 120 capacity scanner (Aperio Technologies, Vista, CA). with ImageScope image browser/annotation tool (Aperio, Vista CA); Access database (Microsoft 2003)/ Oracle 11g database server (Oracle, Redwood Shores, CA); programming language: ColdFusion (Adobe systems, San Jose, CA); Web-based server using Sun1 (Oracle, Redwood Shores, CA)

Design

192 hematopathology conference cases over a one year period were de-identified and pertinent information was entered into an Access database, including clinical information, microscopic description, immunophenotype, flow cytometric histograms, and the results of cytogenetic and molecular studies. WSI were prepared by scanning using a 40X objective (Aperio 120 capacity scanner). WSI and supplemental data were stored on separate servers and referenced in the database via hyperlink. ColdFusion was used to integrate all of the data sources and to provide a seamless front end to the user.

Results

From January 2009 to March 2010, over 4,000 users have accessed the site via the web interface. The pathology trainee can view the list of cases and brief clinical history, with or without the diagnosis displayed. Once a case is chosen, the complete clinical history, as well as WSI and flow cytometry links are displayed, viewed in separate windows, and the user can also scroll down to view the numerical data (complete blood count values, bone marrow differentials, etc), morphologic description, and results of the immunohistochemical and other ancillary studies performed. The diagnosis is shown at the end of the case.

Conclusions

The integrated hematopathology virtual set is emerging as an important tool in hematopathology education. The internet deployed database is readily accessible and robust, enriching the trainee experience. Future directions include development of virtual simulation testing in order to best assess resident's competency and performance in effective utilization of ancillary studies.

Practical Paper Form Replacement With Light-Weight Applications Using Adobe Acrobat

David N. Rundell 1 , Ulysses G.J. Balis 2 , John A. Hamilton 2 , John Perrin 2

1 Scott & White Memorial Hospital, Temple, TX, 2 University of Michigan Health System, Ann Arbor, MI.

E-mail: drundell@gmail.com

Content

All aspects of anatomic and clinical pathology are under pressure to replace paper forms with electronic ordering. In theory, this should reduce errors, provide a more permanent record, and ensure proper delivery and receipt. Electronic ordering also allows timestamping which provides a metric to measure turnaround time. The difficulty of moving to an electronic system are justifying the cost of an information technologist to develop, test and train applications. Moreover, off-the-shelf solutions can be expensive and may not fit the workflow of individual institutions. Our purpose is to show that Adobe Acrobat Professional (retail price $449) can fill in these gaps by creating light-weight applications with dynamic PDF forms.

Technology

Adobe Acrobat Professional 9.0, Live Cycle

Design

An existing paper form for ordering immunohistochemical (IHC) stains was selected for replacement with a light-weight dynamic PDF form using Adobe Acrobat Pro and the bundled Live Cycle application. The goal was to define requirements, implement and test the light-weight form with little prior knowledge of Adobe Acrobat development over three weeks without prior knowledge of the Acrobat development cycle.

Results

Requirements mandate the list of stains and a summary sheet of stains orders be dynamic tables. An XML schema was defined for stain structure to use as a datasource for building the PDF form for ordering. The stains ordered are added to a dynamic summary table which was sent by email to the IHC lab. The PDF form was used at University of Michigan for 8 months. There were substantial time savings in speed of delivery and interpretation by summarizing the orders. In addition, the form gave added benefits of the addition of bar codes and validation of order entry using JavaScript. The form contained timestamps which can be retrieved and interpreted to improve laboratory workflow in the future. The form is currently being modified for use at University of Arkansas.

Conclusion

Adobe Acrobat Professional is a viable and inexpensive solution for light-weight application development for replacing paper forms in Pathology Departments.

Evaluation of Web Based Streaming as a Tool in Telecytology

Gautam Sharma 1 , Gaurav Sharma 1 ,

Abid Shah 2 , Sara Monaco 1 , Walid Khalbuss 1 , Anil Parwani 1 , Ishtiaque Ahmed 1 ,

Liron Pantanowitz 1

1
University of Pittsburgh Medical Center, Department of Pathology Division of Pathology Informatics, Pittsburgh, PA, 2 University of Pittsburgh, Department of Biomedical Informatics, Pittsburgh, PA.

E-mail: gautamsharma7@gmail.com

Content

Telecytology involves the transmission of digital images for remote diagnosis or consultation. Most users currently employ a dynamic telepathology system for this purpose using a live telecommunications link. However, existing challenges with focus and certain morphologies (e.g. neuroendocrine tumor nuclei) remain. We evaluated a real-time telecytology system in the form of web based streaming system (WBSS) and compared its performance to the optical microscope (OM).

Technology

Optical Microscope (Olympus BX51); Microscope Camera (Olympus DP71); WBSS Module (Olympus NetCam Package).

Design

A total of 20 non-gynecological cases from varying organ systems with a spectrum of disease entities were selected from our cytopathology archives. One representative slide (Diff-Quick stain) per case was reviewed by 3 cytopathologists using an OM and desktop computer with WBSS (interim 2 week washout period). The same host (pathology fellow) was used for all sessions. Case complexity, obscuring features, adequacy determination, diagnostic confidence and intra-observer concordance were evaluated for each modality.

Result

A total of 120 encounters were recorded and analyzed. There were significant differences in perception of high image quality (98.3% OM and 28.3% WBSS, p=0.0001), high case complexity (8.3% OM and 21.7% WBSS, p=0.0469), lack of obscured features (88.3% OM and 53.3% WBSS, p=0.0001) and high diagnostic confidence (80% OM and 48.3% WBSS, p=0.0007). No significant difference was observed for perception related to adequacy (81.7% OM and 80% WBSS, p=0.576) and diagnostic concordance (81.7% OM and 75% WBSS, p=0.375). The average review time per case was 70 seconds for OM and 94 seconds for WBSS.

Conclusion

When compared to OM, a WBSS has equivalent diagnostic concordance for telecytology. However, diagnostic confidence is lower with the WBSS where the user's impression of sub-optimal image quality renders cases to appear more complex. Future developments in network capability, imaging technology (e.g. high definition streaming, z-stacked whole slide images) and increased familiarization with remote diagnosis technology are required to enable wider adoption of telecytology.

An Improvised Telemicroscopy System Between the Frozen Section Lab and Operating Room Suites

S. Joseph Sirintrapun, Edward Levine, Vasilios B. Koutras

Wake Forest University Baptist Medical Center, Winston Salem, NC.

E-mail: jsirintr@wfubmc.edu

Content

Frozen section diagnoses are performed with glass slides being evaluated via a microscope in the frozen section lab. At our institution, results of the frozen section are often communicated via telephone. Through various available unused older pieces of equipment, we have improvised a system capable of telemicroscopy which is able to project histology from the frozen section lab microscope into the operating room suites and in addition allow interactive video and audio communication between the surgeon and pathologist.

Technology

The operating room has a fully integrated Carl Storz OR1 system, that has three 26" HD displays mounted from the ceiling. The operating room also has an in-light and wall mounted camera for the frozen section lab to view the operative procedure in progress.

The frozen section lab has Carl Storz H3-M surgical microscope head video camera which supports a 1920 x 1080 with a CCD sensor with a frame rate of 60 fps. Also present in the frozen section lab is a Carl Storz SCB image 1 hub Camera Control Unit, which allows the image to be adjusted. This hub has the capabilities to output to many mediums such as VGA, DVI and SDI Composite and S-Video.

The Rivulet acts as the intermediary between the operating room and frozen section lab. The Rivulet is an older endpoint system which allows for two-way transmission. It offers QOS (Quality of Service) which enable packet priority over the IP network, with no lag or frame loss. Network transmission is 33 Mb per second over a 100 Mb network line. Frame rate is 30 frames per second with a resolution of 480i (720 × 480).

Design

This telemicroscopy system has been used for the evaluation of sentinel lymph node via touch preparations. Images are captured by the camera attached to the microscope, and displayed by the Rivulet device present in the frozen room lab to allow the pathologist to visualize what is transmitted to the operating room. Microscopic images are displayed on the three 26" HD displays mounted from the ceiling of the operating room. The wall mounted camera in the operating room is in turn able to project the operative team and surgical field back to the pathologist via the Rivulet device in the frozen room lab.

Results

Breast sentinel lymph node cases number approximately ten per week with two to three sentinel lymph node touch prep evaluations per each case. Image quality is good considering that the camera is not designed for actual microscopy. Surgeons were readily impressed and have a better understanding of some of the subtle findings which are encountered morphologically on frozen cytologic touch preps. When indefinite diagnoses are rendered, atypical or suspicious cells are more easily explained by transmitted image. There is no lag time, with transmission being nearly immediate. Moreover, the pathologist is able to see the operative field and communicate both audio and visually with the surgeon. Communication between surgeon and pathologist is noticeably more interactive.

Conclusions

The largest unquantifiable benefit of this telemicroscopy system is better communication. With our simple system, intermediaries are eliminated and communication is direct. For pathologists who appreciate communication with surgeons in real-time, the system is a bonus. There are potential plans to expand the technology to other surgical suites and also place the system on the network so that frozen section teleconsultation can be performed with a consulting pathologist whose office is located in a different area of the hospital.

Lessons Learned From Laboratory Information System Downtime Events

Matthew A. Smith, Anil V. Parwani, Anthony Piccoli, Frank J. Losos III, Liron Pantanowitz

University of Pittsburgh Medical Center, Pittsburgh, PA.

E-mail: smithma@upmc.edu

Content

Many groups have studied how the laboratory information system (LIS) improves efficiency and productivity. However, few studies have evaluated details regarding LIS downtimes. The aim of this study was to investigate how often our Anatomical Pathology LIS was down and to evaluate our measures in dealing with and preventing these disruptions to patient care.

Technology

Anatomic Pathology LIS (CoPathPlus, Cerner, v3.2); 6 virtual servers (Central File/Application Server, Image File Storage, Distributed Process and Printing, Distributed Process, PDF Archive, and Report Database); 2 standalone servers (Automated Fax Server and Relational Database(Sybase); Enterprise operating systems (32-bit Windows).

Design

Our Anatomical Pathology LIS reports approximately 7500 results weekly from 200+ concurrent users at 13 sites. The frequency and reasons for our Anatomical Pathology LIS downtimes were investigated over a 5-year period. Procedures used to deal with these downtimes were also reviewed.

Results

Scheduled downtimes occurred originally on Tuesday mornings, 6am-8am and were later moved to weekends from 6am-8am. Longer downtimes required for major system upgrades were scheduled Saturday night through Sunday morning. Scheduled downtimes occurred to improve and expand LIS functionality (e.g., new feature updates) or apply software fixes issued by the vendor. Users were alerted 2 weeks before and then 2 days prior to these outages. For downtimes that extended beyond the scheduled times, updates were sent at 30 minute intervals. Unscheduled downtimes occurred due to contentions between database processes, rare problems with server resources, or non-specific network difficulties. Unscheduled downtimes rarely extended beyond 30 minutes.

Conclusions

Unscheduled downtimes are unavoidable events. Their impact to users can be curtailed by ensuring adequate informatics staff and back up technologic resources are available, and that procedures are followed during such events. Well-planned scheduled downtimes for active maintenance can help prevent significant unscheduled downtimes that may cause major disruptions in patient care.

PathRez - A Web-Based, Searchable Pathology Image and Virtual Slide Database

Roy Somak, Matthew Smith, Frank Fusca, Gary Burdelski, Denine Maglicco, Liron Pantanowitz, Anil Parwani

University of Pittsburgh Medical Center, Pittsburgh, PA.

E-mail: roys911@gmail.com

Content

Online image libraries are a valuable resource for trainees and practicing pathologists. Whole slide images (WSI) have added a new dimension to them. Several online libraries are available, but many lack indexing to allow easy searches. The result is an unsatisfactory user experience due to inefficient process of image searches. Our study aims to build an indexed online pathology atlas.

Technology

PathRez, a web interfaced and indexed SQL server 2008 (Microsoft, Richmond, VA, US) database of images, was built using the. NET framework 4 platform (Microsoft, Richmond, VA, US). HTML, CSS and JavaScript was used for client side scripting and VB.NET was used for server side coding. The search tool was based on a text fragmentation algorithm that enabled partial word and keyword search.

Design

The user interface was rendered at runtime from the information in the database. The simple layout consisted of a header, navigation bar and a content area. The latter displayed browse, search, contribution and feedback pages. Images were displayed using an in-built image viewer or vendor-provided viewers for WSI. Images were assigned a unique ID, based on a 3-tier classification schema, which was used for retrieving them from the database and to de-identify any patient information. The website is currently hosted in the UPMC system and is accessible from work and home (via remote access).

Results

The homepage welcomes the user with a random image from the database, which currently contains over 200 WSIs of genitourinary, pulmonary, infectious disease and cardiac pathology and 200 gross and microscopic images. A brief description with the contributor name of accompanies the latter. The feedback page allows the user to post their comments. The contribution page contains instruction for the submission process.

Conclusion

This web based pathology image library provides a reference database for users at different stages of pathology training and practice. What makes this application unique is the dedicated search function integrated into its design providing quick and relevant results. Such a tool is applicable as an online reference for beginners, instructional resource for tutors, trainee evaluation tool and a forum for sharing interesting images.

Cancer Bench-to-Bedside: A Tool to Enable Data Discovery and Aggregation for Prostate Cancer Biospecimen Informatics Network

Baris E. Suzek 1 , Ian Fore 2 , Juli Klemm 2 ,

Andrew Helsley 3 , Robert Dennis 3 , Jim Humphries 4 , William B. Lander 5 , Rod Winkler 5 , Mukesh Sharma 6 , Paul Fearn 7

1
Georgetown University Medical Center, Biochemistry and Molecular Biology, Washington, DC, 2 National Cancer Institute, Center for Biomedical Informatics and Information Technology, Rockville, MD, 3 David Geffen School of Medicine at University of California, Los Angeles, The Computing Technologies Research Lab, Los Angeles, CA, 4 QuaTeams Inc., Software Engineering, Washington, DC, 5 SAIC-Frederick, Inc., Information System Program Directorate, Rockville, MD, 6 Washington University School of Medicine, Center for Biomedical Informatics, Saint Louis, MO, 7 University of Washington School of Medicine, Medical Education and Biomedical Informatics, Seattle, WA.

E-mail: bes23@georgetown.edu

Content

The Prostate Cancer Specialized Programs of Research Excellence (SPORE) Biospecimen Informatics Network brings together nine academic medical centers, namely Dana-Farber Harvard Cancer Center, Oregon Health Sciences University, University of California-San Francisco, University of Michigan, Sloan-Kettering Cancer Center, Baylor College of Medicine, University of California-Los Angeles, University of Washington and Northwestern University. The objective of this network is to facilitate research and develop new scientific approaches in early detection, diagnosis, treatment, and prognosis of human prostate cancer through data and resource sharing.

A critical need for the network is being able to discover and aggregate de-identified biospecimen data from multiple instances of caTissue Suite; a biorepository tool for biospecimen inventory management, tracking, and annotation, deployed at respective institutions. cancer Bench-to-Bedside (caB2B) is a tool that enables formulation and invocation of metadata based queries against distributed data services - including caTissue Suite instances - using several criteria including clinical and pathology annotations.

Technology

caB2B architecture is primarily Java-based and employs several technologies including Java Swing, Java Platform, Enterprise Edition, Java Struts, JavaServer Pages, asynchronous JavaScript and XML and Adobe Flex.

Design

caB2B is composed of three core components: the Web Application, the Client Application and the Administrative Module. The caB2B Web Application provides query templates that allow easy search and retrieval of data (e.g. Biospecimen) from a federation of services such as caTissue Suite. The caB2B Client Application enables metadata-based query formulation, storage and execution. The Administrative Module provides a graphical user interface for customizing a local instance of caB2B.

Results

caB2B been tested with several example queries to identify biospecimen availability at Prostate SPORE Biospecimen Informatics Network participants using several pathology and clinical annotations. A customized instance of caB2B has been deployed at University of California, Los Angeles and several query templates are being developed for Prostate SPOREs.

Conclusions

caB2B is a tool that addresses the critical need of data discovery and aggregation from a unique community, Prostate SPOREs. The tool will evolve and improve as new requirements are provided by Prostate SPOREs and other communities with similar needs.

Virtual Surgical Pathology Rotation: Development of an Extensive Surgical Pathology Whole Slide Imaging Archive For Pathology Education

Muhammad Syed 1 , Gaurav Sharma 2 , Leonel Edwards 1 , Rina Siddiqui 1 , Liron Pantanowitz 2 , Anil Parwani 2

1
Danbury Hospital, University of Vermont College of Medicine, Danbury, CT, 2 University of Pittsburgh Medical Center, Pittsburgh, PA.

E-mail: asimsyed786@hotmail.com

Content

An important aspect of pathology residency training is to access a variety of tissue samples that will train residents to competently recognize the simplest to most complex diseases. Traditional glass slide teaching sets have limitations such as deterioration of stains and broken or lost slides. The aim of this project was to create an online whole slide image (WSI) archive as a web-based teaching module in surgical pathology. By making over 1,000 high resolutions WSI accessible this web-based module will have a significant impact on pathology residency programs, by expanding the resident's exposure to rare and unusual cases.

Technology

WSI scanner with image browser/annotation tool: Aperio Scanscope XT 120slide loader ImageScope 11.0 Aperio, Vista, CA); hardware server: Quad Core Intel processor, 4 gigabytes RAM, and 10 terabytes storage; database server: Oracle 11g (Oracle, Redwood Shores, CA); web-server: SunOne (Oracle, Redwood Shores, CA); programming language: ColdFusion (Adobe Systems, San Jose,CA).

Design

Over 1,000 glass slides each representing a single surgical pathology case were anonymized, scanned and organized into a digital study set that includes WSI of H&E stains, along with the relevant case history and results of pertinent ancillary studies. Once verified, WSI were published online (https://secure.opi.upmc.edu/boardreview/index.cfm) for registered users.

Results

Over 1,000 glass slides have been digitized and annotated. The time spent scanning and annotating ranged from 5 to 7 minutes per slide. The cases are available to internal users currently. Planned initiatives include expanding case related information, devise a standardized annotation protocol for allowing experts to mark specific findings on WSI, and the creation of entity specific pre/post quiz in a user customizable testing interface.

Conclusion

The surgical pathology digital archive represents a high quality image database that provides wide search and sort capabilities from single organ to multi-organ system study. With additional enhancements, a resident can do a "virtual surgical rotation", test oneself before and after a specific rotation and also prepare for the anatomical pathology board examination.

caTissue Suite 2.0: An Open-Access, Feature-Rich Tool For Biospecimen Annotation And Data Sharing: The Tissue/Biospecimen and Technology Tools Knowledge Center

Mark Watson, Rakesh Nagarajan, Dave Mulvihill

Washington University School of Medicine, St. Louis, MO. E-mail: mwatson@pathology.wustl.edu

Content

Advances in molecular technologies and clinical trial design have mandated new requirements for the operation of biorepostories. caTissue Suite is a caBIG TM application, now in its sixth iterative release, that is designed to manage the complexities of biospecimen annotation data.

Technology

New features and architectural redesign of caTissue Suite 2.0 are based on continued requirements gathering and acceptability testing by the biobanking community across multiple institutions worldwide. caTissue uses a web browser to store and retrieve data from a database. Its open program interface (API) permits customized access to all of the application's features, and data integration from other data systems. The technology stack for caTissue 2.0 include: JBoss 5.1.0 GA, Java JDK 1.6, MySQL 5.1.x or Oracle 10.2.0.2.0 and Ant 1.7.

Design

The application supports role-based access to administrative functions, biospecimen accessioning, and investigator queries. caTissue Suite 2.0 (scheduled for release in the first quarter of 2012) includes several usability enhancements and a new functionality to define and record specimen processing procedures and events in the biospecimen life cycle. In addition, caTissue Suite 2.0 provides interoperability with the NCI's Clinical Trial Reporting Program (CTRP), has improved caGrid operability, and allows for the export of biospecimen data in MAGE-TAB format, suitable for use with other integrative cancer research tools such as caArray.

Results

caTissue Suite is sufficiently scalable and configurable for broad deployment across biorepostories of varying size and function. Numerous institutions have adopted the application and are using it in their daily operations. A caBIG TM supported, web-based "Knowledge Center" (https://cabig-kc.nci.nih.gov/Biospecimen/KC) provides on-going application support via discussion forums, technical and user guides, training tools, and webinars.

Conclusion

caTissue Suite is a freely available, fully supported, open-access software application for biospecimen data management. The official version 1.2 application release and a demonstration version 2.0 are available at the Knowledge Center web site. Use of caTissue Suite by several NCI Cancer Centers and other biospecimen resource groups is providing a rapid and facilitated path toward standardizing biospecimen informatics and promoting biospecimen data sharing both nationally and globally.

Prediction of Combined CYP2C19/PON1 Genotype Effect on Clopidogrel Response

Lu Yang, Mark W. Linder

University of Louisville, Louisville, KY.

E-mail: 10yang05@gwise.louisville.edu

Content

Cytochrome P450 2C19 (CYP2C19) is a determining genetic factor accounting for variable response to clopidogrel among patients undergoing percutaneous coronary intervention (PCI). Paraoxonase 1 (PON1) was recently reported as perhaps a second factor. CYP2C19*2 allele and PON1 Q allele are identified as risk factors for stent thrombosis (ST) independently. The combined effect of these independent genetic factors has not been tested.

Technology

Genetic risk calculations were performed independently for CYP2C19 and PON1 variants groups. A multiplicative model was applied to predict the impact of the combined CYP2C19/PON1 genotype on clopidogrel's clinical efficacy, which is believed to fit the real data for many common diseases. The prevalence of combined genotypes among stent thrombosis (ST) patients was then calculated.

Design

Literature search was conducted to review the effect of CYP2C19 and PON1 genetic variants on clopidogrel efficacy in the context of PCI. Individual risk informatics data were extracted and analyzed from the chosen studies for studying the combined genotype effect.

Results

In our analysis, the risk of ST after PCI for the general population regardless of genotypes is set at 1 and used as the baseline risk value. Four combined genotypes showed a higher than 1 relative risk value: CYP2C19*2*2/PON1 QQ (7.84), CYP2C19*1*2/PON1 QQ (2.91), CYP2C19*2*2/PON1 QR (2.66) and CYP2C19*1*1/PON1 QQ (1.11). Consequently, CYP2C19*1*1/PON1 QQ, which has previously been reported as showing lower risk of ST based on CYP2C19*1 low risk allele only, is considered now as potential risk population by the combined genotype analysis. In contrast, CYP2C19*1*2/PON1 RR and CYP2C19*2*2/PON1 RR now are in the low risk group while they used to be identified by CYP2C19*2 risk allele as at higher risk for ST. The most prevalent combined genotype accounting for about 33.2% patients experiencing ST after PCI is CYP2C19*1*1/PON1 QQ while the least prevalent genotype is CYP2C19*2*2/ PON1 RR(0.27%).

Conclusions

Our study provides insights into understanding the role of genetic variants in heterogeneity of clopidogrel response to the stent procedure. This theoretical analysis can be used to generate quantitative hypotheses for future studies planning to evaluate the interaction of two genetic variants on a common clinical endpoint.








 

 
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