Leif Neve

Age-Related Changes of the Cervix Influence Human Papillomavirus Type Distribution

Approximately 15 human papillomavirus (HPV) types cause virtually all cervical cancer whereas other HPV types are unrelated to cancer. We were interested in whether some noncarcinogenic types differ from carcinogenic in their affinity for the cervical transformation zone, where nearly all HPV-induced cancers occur. To examine this possibility, we tested cervical specimens from 8,374 women without cervical precancer and cancer participating in a population-based study in Guanacaste for >40 HPV types using PCR. We compared age-group specific prevalences of HPV types of the alpha9 species, which are mainly carcinogenic and include HPV16, to the genetically distinct types of the alpha3/alpha15 species (e.g., HPV71), which are noncarcinogenic and common in vaginal specimens from hysterectomized women. We related HPV detection of each group to the location of the junction between the squamous epithelium of the ectocervix and vagina and the columnar epithelium of the endocervical canal. Models evaluated the independent effects of amount of exposed columnar epithelium (ectopy) and age on the presence of alpha9 or alpha3/alpha15 types. Prevalence of alpha9 types (7.6%) peaked in the youngest women, declined in middle-aged women, and then increased slightly in older women. By contrast, prevalence of alpha3/alpha15 types (7.6%) tended to remain invariant or to increase with increasing age. Detection of alpha9 infections increased (P(trend) < 0.0005) but alpha3/alpha15 infections decreased (P(trend) < 0.0005) with increasing exposure of the columnar epithelia. Older age and decreasing cervical ectopy were independently positively associated with having an alpha3/alpha15 infection compared with having an alpha9 infection. These patterns need to be confirmed in other studies and populations. We suggest that these genetically distinct groups of HPV types may differ in tissue preferences, which may contribute to their differences in carcinogenic potential.

The accuracy of colposcopic grading for detection of high-grade cervical intraepithelial neoplasia

Objective. To relate aspects of online colposcopic image assessment to the diagnosis of grades 2 and 3 cervical intraepithelial neoplasia (CIN 2+). Methods: To simulate colposcopic assessment, we obtained digitized cervical images at enrollment after acetic acid application from 919 women referred for equivocal or minor cytologic abnormalities into the ASCUS-LSIL Triage Study. For each, 2 randomly assigned evaluators from a pool of 20 colposcopists assessed images using a standardized tool online. We calculated the accuracy of these assessments for predicting histologic CIN 2+ over the 2 years of study. For validation, a subset of online results was compared with same-day enrollment colposcopic assessments. Results. Identifying any acetowhite lesion in images yielded high sensitivity: 93% of women with CIN 2+ had at least 1 acetowhite lesion. However, 74% of women without CIN 2+ also had acetowhitening, regardless of human papillomavirus status. The sensitivity for CIN 2+ of an online colpophotographic assessment of high-grade disease was 39%. The sensitivity for CIN 2+ of a high-grade diagnosis by Reid Index scoring was 30%, and individual Reid Index component scores had similar levels of sensitivity and specificity. The performance of online assessment was not meaningfully different from that of same-day enrollment colposcopy, suggesting that these approaches have similar utility. Conclusions. Finding acetowhite lesions identifies women with CIN 2+, but using subtler colposcopic characteristics to grade lesions is insensitive. All acetowhite lesions should be assessed with biopsy to maximize sensitivity of colposcopic diagnosis with good specificity.

SPIRS: A Web-based Image Retrieval System for Large Biomedical Databases

PURPOSE With the increasing use of images in disease research, education, and clinical medicine, the need for methods that effectively archive, query, and retrieve these images by their content is underscored. This paper describes the implementation of a Web-based retrieval system called SPIRS (Spine Pathology & Image Retrieval System), which permits exploration of a large biomedical database of digitized spine X-ray images and data from a national health survey using a combination of visual and textual queries. METHODS SPIRS is a generalizable framework that consists of four components: a client applet, a gateway, an indexing and retrieval system, and a database of images and associated text data. The prototype system is demonstrated using text and imaging data collected as part of the second U.S. National Health and Nutrition Examination Survey (NHANES II). Users search the image data by providing a sketch of the vertebral outline or selecting an example vertebral image and some relevant text parameters. Pertinent pathology on the image/sketch can be annotated and weighted to indicate importance. RESULTS During the course of development, we explored different algorithms to perform functions such as segmentation, indexing, and retrieval. Each algorithm was tested individually and then implemented as part of SPIRS. To evaluate the overall system, we first tested the systems ability to return similar vertebral shapes from the database given a query shape. Initial evaluations using visual queries only (no text) have shown that the system achieves up to 68% accuracy in finding images in the database that exhibit similar abnormality type and severity. Relevance feedback mechanisms have been shown to increase accuracy by an additional 22% after three iterations. While we primarily demonstrate this system in the context of retrieving vertebral shape, our framework has also been adapted to search a collection of 100,000 uterine cervix images to study the progression of cervical cancer. CONCLUSIONS SPIRS is automated, easily accessible, and integratable with other complementary information retrieval systems. The system supports the ability for users to intuitively query large amounts of imaging data by providing visual examples and text keywords and has beneficial implications in the areas of research, education, and patient care.

Digital tools for collecting data from cervigrams for research and training in colposcopy.

Abstract: Colposcopy is a critical part of gynecologic practice but has documented deficiencies, including lack of correlation between the colposcopic appearance and the severity of underlying neoplasia, limited reproducibility, and difficulty in the optimal placement of colposcopically directed biopsies. In a collaborative effort to improve colposcopy, we are analyzing digitized cervigram images from National Cancer Institute-funded studies. Specifically, the National Cancer Institute has collected close to 100,000 cervigrams, digitized to create a database of images of the uterine cervix for research, training, and education. In addition to the cervigram images, this database contains clinical, cytologic, and molecular information at multiple examinations of 15,000 women, with password and ID labeling strategies to protect patient privacy. The National Library of Medicine has designed two web-accessible software tools. The Boundary Marking Tool allows experts on colposcopy to perform an evaluation of the pictures and to mark boundary regions of normal and abnormal regions of the uterine cervix; these evaluations are collected and saved in the database. The Multimedia Database Tool enables retrieval of test and image biomedical data according to specific queries, for example, all women with cervical intraepithelial neoplasia 3 whose cytologic results are atypical squamous cells of undetermined significance. The resource soon will be available as an open resource, via a teaching tool coordinated by a database manager, which will permit a variety of applications for teaching and research. In this article, we describe the perceived need for the resource and its components.

WebMIRS: Web-based medical information retrieval system

At the Lister Hill National Center for Biomedical Communications, a research and development division of the National Library of Medicine (NLM), we are developing a prototype multimedia database system to provide World Wide Web access to biomedical databases. WebMIRS (Web-based Medical Information Retrieval System) will allow access to databases containing text and images and will allow database query by standard SQL, by image content, or by a combination of the two. The system is being developed in the form of Java applets, which will communicate with the Informix DBMS on an NLM Sun workstation running the Solaris operating system. The system architecture will allow access from any hardware platform, which supports a Java-enabled Web browser, such as Netscape or Internet Explorer. Initial databases will include data from two national health surveys conducted by the National Center for Health Statistics (NCHS), and will include x-ray images from those surveys. In addition to describing in- house research in database access systems, this paper describes ongoing work toward querying by image content. Image content search capability will include capability to search for x-ray images similar to an input image with respect to vertebral morphometry used to characterize features such as fractures and disc space narrowing.

Interfacing Global and Local CBIR Systems for Medical Image Retrieval

Contemporary picture archiving and communication systems are limited in managing large and varied image collections, because content-based image retrieval (CBIR) methods are unavailable. In this paper, an XML-based data and resource exchange framework is defined using open standards and software to enable specialized CBIR systems to act as geographically distributed toolkits. The approach enables communication and collaboration between two or more geographically separated complementary systems with possibly different architectures and developed on different platforms, and specialized for different image modalities and characteristics. The resulting synergy provides the user with a rich functionality operating within a familiar Web browser interface, making the combined system portable and independent of location and underlying user operating systems. We describe the coupling of the Image Retrieval in Medical Applications (IRMA) system and the Spine Pathology and Image Retrieval System (SPIRS) as proof of this concept.

World Wide Web platform-independent access to biomedical text/image databases

The biomedical digital library of the future is expected to provide access to stores of biomedical database information containing text and images. Developing efficient methods for accessing such databases is a research effort at the Lister Hill National Center for Biomedical Communications of the National Library of Medicine. In this paper we examine issues in providing access to databases across the Web and describe a tool we have developed: the Web-based Medical Information Retrieval System (WebMIRS). We address a number of critical issues, including preservation of data integrity, efficient database design, access to documentation, quality of query and results interfaces, capability to export results to other software, and exploitation of multimedia data. WebMIRS is implemented as a Java applet that allows database access to text and to associated image data, without requiring any user software beyond a standard Web browser. The applet implementation allows WebMIRS to run on any hardware platform (such as PCs, the Macintosh, or Unix machines) which supports a Java-enabled Web browser, such as Netscape or Internet Explorer. WebMIRS is being tested on text/x-ray image databases created from the National Health and Nutrition Examination Surveys (NHANES) data collected by the National Center for Health Statistics.

Digital atlas for spinal x rays

At the National Library of Medicine we are developing a digital atlas to serve as a reference tool for the interpretation of cervical and lumbar spine x-rays. The atlas contains representative images for four grades of severity for cervical/lumbar spondylolisthesis. A prototype version of the atlas has been built using images for which expert rheumatologist readers reached exact agreement in grading. The atlas functionality includes the ability to display cervical and lumbar anatomy, display of single images or multiple simultaneous images, image processing functions, and capability to ad user-defined images to the atlas. Images are selected for display by the user specifying feature and grade. Currently, the atlas runs on a Sun SPARC workstation under the Solaris operating system. THe initial use of the atlas is to aid in reading a collection of 17,000 NHANES II digitized x-rays. The atlas may also be used as a general digital reference tool for the standardized interpretation of digital x-rays for osteoarthritis. We are investigating further development of the atlas to accommodate a wider set of images, to operate on multiple platforms, and to be accessible via the WWW.

Preparing digitized cervigrams for colposcopy research and education: determination of optimal resolution and compression parameters.

Objective Visual assessment of digitized cervigrams through the Internet needs to be optimized. The National Cancer Institute and National Library of Medicine are involved in a large effort to improve colposcopic assessment and, in preparation, are conducting methodologic research. Materials and Methods We selected 50 cervigrams with diagnoses ranging from normal to cervical intraepithelial neoplasia 3 or invasive cancer. Those pictures were scanned at 5 resolution levels from 1,550 to 4,000 dots per inch (dpi) and were presented to 4 expert colposcopists to assess image quality. After the ideal resolution level was determined, pictures were compressed at 7 compression ratios from 20:1 to 80:1 to determine the optimal level of compression that permitted full assessment of key visual details. Results There were no statistically significant differences between the 3,000 and 4,000 dpi pictures. At 2,000 dpi resolution, only one colposcopist found a slightly statistically significant difference (p = 0.02) compared with the gold standard. There was a clear loss of quality of the pictures at 1,660 dpi. At compression ratio 60:1, 3 of 4 evaluators found statistically significant differences when comparing against the gold standard. Conclusions Our results suggest that 2,000 dpi is the optimal level for digitizing cervigrams, and the optimal compression ratio is 50:1 using a novel wavelet-based technology. At these parameters, pictures have no significant differences with the gold standard.

Application-level technique for faster transmission of large images on the internet

An application-level technique for improving the transmission rate of large files is described in this paper. Such techniques are important in areas such as telemedicine, where near-real-time delivery of large files such as digital images is a goal: end users may include specialist whose time is scarce and expensive, and timely access to the data may be necessary for effective clinical treatment. Faster delivery is also an enabling technology for accessing remote medial archives. In conventional TCP/IP transmission, data to be transmitted is sent down one logical communication channel. Our technique divided the data into segments; each segment is sent down its own channel, and the segments are reassembled into a copy of the original data at the receiving end. This technique has been implemented and tested in a client-server program using Berkeley Unix sockets, multiple independent process for channel control, and interprocess communication techniques to guarantee the receipt and correct reassembly of the transmitted data. Performance measurements have been made on several hundred Internet transmissions (including Arizona-to-Maryland transmissions) of 5-megabyte cervical x- ray images. Transmission time as a function of number of channels has been recorded, and a 3-fold improvement in transmission rate has been observed.