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Biomedical subjects

Peter H Bartels

Publications and source records attributed to Peter H Bartels.

At least 19 recordsLinked to original sources

Carcinogenesis and the hypothesis of phylogenetic reversion.

Chemoprevention must target early molecular events involved in malignant transformation. The sequence of events leading from a normally functioning interphase cell to an uncontrolled tumor cell is only partially understood, impeding systematic design of chemopreventive agents. The respective roles of mutagenic and epigenetic mechanisms have not been definitively established. Also, traditional models do not appear to incorporate cellular response to events leading to carcinogenesis. A perspective on system response offered by complexity science elucidates the roles of feedback and control in maintaining functional stability during carcinogenesis. Carcinogenesis is seen as a process of epigenetic redifferentiation resulting in a cell behaving like an archetypal karyocyte free of growth restraints (phylogenetic reversion). Genes that evolved during the development of multicellular organisms, restraining uncontrolled growth and regulating intercell communication may be systematically silenced during carcinogenesis. The formation of heterochromatin, which results in epigenetic silencing by hypermethylation in CpG-dense islands, finds expression in the nuclear chromatin pattern. Karyometry is an integrating biomarker of chromatin pattern information that accommodates the possibility of multiple, differently ordered pathways and provides exquisite sensitivity, allowing detection of very early transformation events. Its use can monitor the impact of chemopreventive agents on the earliest events in progression to cancer.

Animals↗

Exploratory study of ovarian intraepithelial neoplasia.

PURPOSE: This was an exploratory study to test two hypotheses related to potential epithelial precursors to ovarian cancer: (a) histologically normal ovarian surface epithelium exhibited changes in the nuclear chromatin pattern, which indicate an ovarian abnormality, and (b) such changes were detectable in the ovarian surface epithelium of cancer-free subjects who were at high risk for ovarian cancer. EXPERIMENTAL DESIGN: Ovaries were carefully collected to avoid damage to the surface epithelium. Five-micron-thick histologic sections were cut and stained with H&E. High-resolution images were recorded from the ovarian surface epithelium and from the underlying stroma of ovaries from normal women (10 cases), women at high risk of developing ovarian cancer (7 cases), and histologically normal areas adjacent to ovarian cancer (3 cases). Karyometric features and measurements of nuclear abnormality were computed for 3,390 epithelial nuclei. Discriminant function analyses and unsupervised learning algorithms were employed to define deviations from normal and to identify the subpopulations of nuclei exhibiting these changes. RESULTS: Epithelium from ovaries harboring a malignant lesion had changes in the nuclear chromatin pattern consistent with a second phenotype, which were not visually detected with histopathologic surveillance. This phenotype was also present in the ovaries obtained from women at increased risk of ovarian cancer, suggesting that it may represent a premalignant abnormality. These changes were statistically significant. CONCLUSION: The observed changes in karyometric features were sufficiently distinct to warrant further study as both diagnostic and prognostic biomarkers for early detection and prevention of ovarian cancer.

Carcinoma in Situ↗

Second order discriminant analysis in chemopreventive efficacy measurement.

OBJECTIVE: To describe the use of second order discriminant analysis as a classification methodology along with the underlying assumptions and sampling requirements, with special emphasis on the use of this analysis in chemopreventive efficacy studies. STUDY DESIGN: The discriminant function score distributions derived in an analysis of 2 diagnostic groups may show such overlap that a statistically significant difference in mean values cannot be shown and, more important, that a useful case-based classification cannot be attained. By using the discriminant function score distributions from each case, it is frequently possible to derive a second order discriminant function based on case-specific characteristics, rather than characteristics of nuclei, thereby attaining improved case classification. RESULTS: Second order discriminant analysis has proven very useful in the documentation of case-level efficacy in chemopreventive trials. In a study of orally administered vitamin A, a first order discriminant analysis did not achieve a statistically significant difference in the score distributions for nuclei, but a second order discriminant analysis allowed a correct recognition of intervention effects in 85% of submitted cases. In a chemopreventive study of triamcinolone, a similarly inadequate discrimination based on discriminant function scores for nuclei resulted. After a second order discriminant analysis, a reduction in solar-actinic damage could be shown in 14/15, or 93%, of treated cases. CONCLUSION: Second order discriminant analysis can be highly effective when the discriminating information offered at the nuclear level is inadequate due to high dispersion and small differences in mean values of discriminant function scores for the diagnostic groups. Second order analysis utilizes case-specific characteristics of the discriminant function score distributions to document diagnostic group separation and/or efficacy of chemopreventive intervention by a reduction in case discriminant function scores.

Administration, Oral↗

Karyometry in rectal mucosa of patients with previous colorectal adenomas.

OBJECTIVE: To determine whether karyometric measurements taken in biopsies from histologically normal-appearing rectal mucosa could serve as a biomarker for the risk of recurrence of polyps. MATERIALS AND METHODS: Biopsies were taken from the rectal mucosa of cases with a prior history of colonic polyps at the baseline of the study. In 57 cases recurrent polyps occurred (R cases); in 72 cases no recurrent disease was found at the end of the study (NR cases). From each biopsy 100 nuclei were recorded at high resolution. After segmentation, feature extraction and selection of a discriminating subset of features, a number of discriminant functions were derived. Also, measures of nuclear abnormality were computed. RESULTS: The differences in karyometricfeature values for nuclei from biopsies of cases with recurrent or nonrecurrent disease were very small and not notably expressed in the majority of nuclei. It was possible by focusing on nuclei showing clear deviations from normal to derive a discriminant function that exhibited a shift for the NR and R data sets. The distributions of discriminant function scores were then subjected to a second-order discriminant analysis to separate cases according to recurrence status. This function showed a statistically highly significant correlation with recurrence. At one extreme of its score distribution were 11 of 57 cases that had a recurrence, and at the other extreme were 8-10 of 72 cases that had no recurrence. The distributions of nuclear abnormality values for these subsets of cases were drastically different, with an average value of 1.72 for the group that may be at high risk for another recurrence and 1.02 for the group possibly at low risk. All cases with a prior history of colonic polyps showed a nuclear abnormality deviating from normal. CONCLUSION: Measurement of a sample of 100 nuclei from the rectal mucosa will suggest, for approximately 10% of cases, that a high risk for recurrence of adenomatous polyps exists and, for a slightly lower proportion, confirm that the nuclei deviate only slightly from those from individuals with no history of colonic polyps. For the majority of cases with a prior history of adenoma, the nuclei in the biopsy show a notable deviation from normal, but the deviation is practically the same for cases that had a recurrence and those that did not. However, a tentative discriminant function (DF I,3) derived from the characteristics of the extreme cases correctly classified approximately 64% of nonrecurrent and 83% of recurrent cases using a Bayesian decision boundary.

Adenomatous Polyposis Coli↗

Karyometry of infiltrating breast lesions.

OBJECTIVE: To characterize nuclei from well-differentiated, moderately differentiated and poorly differentiated lesions of invasive breast cancer by karyometry and to test the hypothesis that these diagnostic categories form homogeneous sets. STUDY DESIGN: Histopathologic sections from 6 cases of well-differentiated, 11 cases of moderately differentiated and 17 cases of poorly differentiated ductal carcinomas were digitally recorded. From each case 100 nuclei were segmented and analyzed by karyometry. A discriminant analysis was performed, and nuclear and lesion signatures were computed. The nonsupervised learning algorithm P-index was applied. A progression curve per diagnostic category based on mean nuclear abnormality and a discriminant function score was derived. RESULTS: The well-differentiated lesions formed a homogeneous set, but both the moderately and poorly differentiated lesions showed 2 significantly different subpopulations with nuclei of substantially different nuclear abnormality and progression. CONCLUSION: The visual histopathologic diagnostic assessment of these lesions was based on an evaluation of both tissue architectural criteria and nuclear criteria. Here, only the pattern of nuclear chromatin was evaluated. Cases belonging to the same diagnostic category as assessed by their differentiation may be further characterized by the extent to which the nuclei deviate from normal. There was substantial case-to-case heterogeneity in these invasive lesions.

Breast Neoplasms↗

The evolution of scanning microphotometry: a historical review.

This article traces the evolution of scanning microphotometry from its beginning, with an emphasis on the developing technologies that have made feasible the rapid and detailed capture of high-resolution image information. Consideration is given to future directions that may prove fruitful to clinical practice.

History, 20th Century↗

The use of morphological characteristics and texture analysis in the identification of tissue composition in prostatic neoplasia.

Quantitative examination of prostate histology offers clues in the diagnostic classification of lesions and in the prediction of response to treatment and prognosis. To facilitate the collection of quantitative data, the development of machine vision systems is necessary. This study explored the use of imaging for identifying tissue abnormalities in prostate histology. Medium-power histological scenes were recorded from whole-mount radical prostatectomy sections at x 40 objective magnification and assessed by a pathologist as exhibiting stroma, normal tissue (nonneoplastic epithelial component), or prostatic carcinoma (PCa). A machine vision system was developed that divided the scenes into subregions of 100 x 100 pixels and subjected each to image-processing techniques. Analysis of morphological characteristics allowed the identification of normal tissue. Analysis of image texture demonstrated that Haralick feature 4 was the most suitable for discriminating stroma from PCa. Using these morphological and texture measurements, it was possible to define a classification scheme for each subregion. The machine vision system is designed to integrate these classification rules and generate digital maps of tissue composition from the classification of subregions; 79.3% of subregions were correctly classified. Established classification rates have demonstrated the validity of the methodology on small scenes; a logical extension was to apply the methodology to whole slide images via scanning technology. The machine vision system is capable of classifying these images. The machine vision system developed in this project facilitates the exploration of morphological and texture characteristics in quantifying tissue composition. It also illustrates the potential of quantitative methods to provide highly discriminatory information in the automated identification of prostatic lesions using computer vision.

Humans↗

An array microscope for ultrarapid virtual slide processing and telepathology. Design, fabrication, and validation study.

This paper describes the design and fabrication of a novel array microscope for the first ultrarapid virtual slide processor (DMetrix DX-40 digital slide scanner). The array microscope optics consists of a stack of three 80-element 10 x 8-lenslet arrays, constituting a "lenslet array ensemble." The lenslet array ensemble is positioned over a glass slide. Uniquely shaped lenses in each of the lenslet arrays, arranged perpendicular to the glass slide constitute a single "miniaturized microscope." A high-pixel-density image sensor is attached to the top of the lenslet array ensemble. In operation, the lenslet array ensemble is transported by a motorized mechanism relative to the long axis of a glass slide. Each of the 80 miniaturized microscopes has a lateral field of view of 250 microns. The microscopes of each row of the array are offset from the microscopes in other rows. Scanning a glass slide with the array microscope produces seamless two-dimensional image data of the entire slide, that is, a virtual slide. The optical system has a numerical aperture of N.A.= 0.65, scans slides at a rate of 3 mm per second, and accrues up to 3,000 images per second from each of the 80 miniaturized microscopes. In the ultrarapid virtual slide processing cycle, the time for image acquisition takes 58 seconds for a 2.25 cm2 tissue section. An automatic slide loader enables the scanner to process up to 40 slides per hour without operator intervention. Slide scanning and image processing are done concurrently so that post-scan processing is eliminated. A virtual slide can be viewed over the Internet immediately after the scanning is complete. A validation study compared the diagnostic accuracy of pathologist case readers using array microscopy (with images viewed as virtual slides) and conventional light microscopy. Four senior pathologists diagnosed 30 breast surgical pathology cases each using both imaging modes, but on separate occasions. Of 120 case reads by array microscopy, there were 3 incorrect diagnoses, all of which were made on difficult cases with equivocal diagnoses by light microscopy. There was a strong correlation between array microscopy vs. "truth" diagnoses based on surgical pathology reports. The kappa statistic for the array microscopy vs. truth was 0.96, which is highly significant (z=10.33, p <0.001). There was no statistically significant difference between rates of agreement with truth between array microscopy and light microscopy (z=0.134, p >0.05). Array microscopy and light microscopy did not differ significantly with respect to the number/percent of correct decisions rendered (t=0.552, p=0.6376) or equivocal decisions rendered (t=2.449, p=0.0917). Pathologists rated 95.8% of array microscopy virtual slide images as good or excellent. None were rated as poor. The mean viewing time for a DMetrix virtual slide was 1.16 minutes. The DMetrix virtual slide processor has been found to reduce the virtual slide processing cycle more than 10 fold, as compared with other virtual slide systems reported to date. The virtual slide images are of high quality and suitable for diagnostic pathology, second opinions, expert opinions, clinical trials, education, and research.

Equipment Design↗

Karyometry detects subvisual differences in chromatin organization state between cribriform and flat high-grade prostatic intraepithelial neoplasia.

This digital texture analysis-based study evaluates the chromatin organization state in flat and cribriform high-grade prostatic intraepithelial neoplasia (PIN), in the adjacent normal looking secretory epithelium and in the co-occurring adenocarcinoma. Digital texture analysis (karyometry) was carried out on hematoxylin and eosin-stained sections from 24 radical prostatectomy specimens with high-grade PIN (12 with flat and 12 with cribriform architectural pattern, respectively) and cancer. Quantification was also conducted on the normal looking secretory epithelium. Discriminant analysis and the nonsupervised learning algorithm P-index were used to identify suitable subsets of features useful for the discrimination and classification of pathological groups and to explore multivariate data structure in the pathological subgroups. The average nuclear abnormality increases monotonically from the histologically normal appearing secretory epithelium to high-grade PIN and to adenocarcinoma. The nuclei from the so-called perimeter compartment of the flat high-grade PIN lesions show a higher nuclear abnormality compared to the nuclei of the cribriform high-grade PINs. Discriminant analysis shows that flat and cribriform high-grade PINs fall into two populations. Processing by the nonsupervised learning algorithm P-index revealed the existence of three well-defined, distinct subpopulations of nuclei of different chromatin phenotype. In the flat high-grade PIN lesions the proportions of nuclei in the three subpopulations are 16.5% (low abnormality), 25.0% (mid abnormality) and 58.5% (high abnormality), respectively. In the cribriform high-grade PIN lesions, 100% of the nuclei are in the mid-abnormality subpopulation. These differences are also discernible in the co-occurring adenocarcinoma and the histologically normal appearing secretory epithelium. To conclude, karyometry and statistical analysis detect the existence of distinct cell subpopulations of different chromatin packaging and phenotype, with the nuclei from the flat high-grade PIN lesions, adjacent normal looking epithelium and co-occurring adenocarcinoma expressing a greater nuclear abnormality than in the specimens with cribriform high-grade PIN.

Cell Nucleus↗

Karyometric features of low and high grade glial tumors as compared with their MRI appearance.

OBJECTIVE: To compare the results of a magnetic resonance imaging (MRI) grading designed to identify low and high grade gliomas with karyometry used as a tool to grade primary brain tumors. STUDY DESIGN: A consecutive series of 23 primary brain tumors was selected for this study. The neuroradiologist, not knowing the histologic diagnoses, divided the cases into low and high grade categories on the basis of the following 7 features: border sharpness, heterogeneity without contrast, cavitation, contrast enhancement, hypervascularity, mass effect and perifocal T2 hyperintensity. To each feature was given a numerical value, ranging from 1 to 3. All the cases were reviewed and classified by the same pathologist, blinded to the MRI diagnosis. Two hundred nuclei per case were recorded, and 93 karyometric features related to nuclear area, total optical density and chromatin distribution were analyzed for each nucleus. Statistical analysis included discriminant analysis, Kruskal-Wallis test, nonsupervised learning algorithm P-index and Beale statistic. RESULTS: Ten cases were classified as low grade on the basis of their MRI features. The corresponding histopathologic diagnoses were: grade 2 astrocytoma in 2 cases and grade 2 oligodendroglioma in 8 cases. An MRI diagnosis of high grade tumor was made in 13 cases. In 10 cases it was confirmed by the histopathologic diagnosis (3 grade 3 astrocytomas, 1 grade 3 oligodendroglioma and 6 glioblastomas). In the remaining 3 cases the histologic examination revealed a low grade tumor, 1 grade 2 astrocytoma and 2 grade 2 oligodendrogliomas. For the purposes of the karyometric analysis the cases were allocated to the low or high grade category according to their histologic diagnosis (13 cases low grade and 10 cases high grade). Nuclei from low and high grade tumors showed clearly different karyometric characteristics. The oligodendroglioma nuclei had abnormality values close to the low grade standard, while the astrocytoma nuclei were a highly dispersed group with characteristics indicative of a higher degree of nuclear abnormality than the oligodendroglioma nuclei. The results of karyometric analysis showed that grade 2 tumors, corresponding to the low grade group, form a rather distinct category from grade 3 and 4 tumors belonging to the high grade group. CONCLUSION: The results of MRI grading based on a series of features that are routinely assessed by the neuroradiologist to reach a final diagnosis correlate highly with the histopathologic diagnosis. Karyometry can be a useful adjunct to histologic grading.

Astrocytoma↗

Karyometric image analysis for intraepithelial and invasive cervical lesions.

OBJECTIVE: To derive an objective, numeric measure for the progression of intraepithelial and invasive squamous cell cervical lesions. STUDY DESIGN: Thin-layer cervical cytology preparations from colposcopically confirmed normal cervix, low grade squamous intraepithelial lesions, high grade squamous intraepithelial lesions and carcinoma were identified from a cross-sectional study. Fifty-nine cases representing 4 diagnostic categories were selected, and 2,375 nuclei from epithelial cells representative of the diagnostic category were randomly selected for imaging and measurement from these cases. Additionally, 1,378 visually normal appearing intermediate cells from low and high grade squamous intraepithelial lesions, as well as from carcinoma cases, were identified for analysis. The nuclei were quantitatively characterized, and discriminant analyses were performed to derive a progression curve from normal cytology to carcinoma. RESULTS: The lesion signatures show a clear increase in nuclear abnormality with increasing progression. A progression curve was derived based on mean discriminant function scores for each diagnostic category and on the mean nuclear abnormality values for the nuclei in each category, as expressed by their deviation in feature values from normal reference nuclei. CONCLUSION: A numeric assessment of lesion progression for cervical precancerous and cancerous lesions based on karyometric measurements is possible and may provide an objective, precise characterization of each lesion as well as a basis for improved performance in automated cytology-based cervical cancer screening.

Cell Nucleus↗

Karyometric analysis of actinic damage in unexposed and sun-exposed skin and in actinic keratoses in untreated individuals.

OBJECTIVE: To assess the ability of karyometric analysis to demonstrate progression of actinic damage as a function of sun exposure in individuals with actinic keratoses (AKs) and to evaluate the stability of that assessment over a 3-month period. STUDY DESIGN: Biopsies from subjects with AKs were obtained from unexposed skin, sun-exposed skin and AK lesions. Subjects used an SPF 50 sunscreen, and 3 months later additional biopsies were taken from sun-exposed and AK sites. A total of 13,300 nuclei were recorded from 31 subjects. RESULTS: Measures of nuclear abnormality (NA) and effects of sun damage based on discriminant function (DF) scores were derived. Actinic damage levels varied significantly across biopsy site, demonstrating the method's sensitivity. Accrual of actinic damage was demonstrated in sun-exposed skin and AK lesions when all nuclei were examined over 3 months but only for sun-exposed skin when the worst-damaged nuclei were examined. This suggests a ceiling effect of nuclear damage in the progression to abnormality. Within-subject variability was similar for both NA and DF when all nuclei were considered. Among the worst-damaged nuclei (as defined by high DF), DF showed lower within-case variability than NA, perhaps due to a reduction in nuclear heterogeneity. CONCLUSION: Karyometry's ability to detect subtle levels of actinic damage in nuclear chromatin patterns may make it useful in screening agents for possible use in cancer chemoprevention.

Actins↗

Preneoplastic changes in ovarian tissues.

OBJECTIVE: To test whether histologically normal epithelium within ovarian inclusion cysts and stroma exhibit changes in nuclear chromatin pattern that indicate the presence of occult ovarian lesions. STUDY DESIGN: Ovaries were collected from 10 low-risk women,from 7 high-risk women and from 3 women with ovarian cancer. Histologic sections were cut at 5 microm and hematoxylin and eosin stained. High-resolution images were recorded from the epithelium lining inclusion cysts and from the underlying stroma of ovaries from these 20 subjects. A total of 2860 epithelial nuclei and 3610 stromal nuclei were recorded. Karyometric features and nuclear abnormality were computed. Discriminant analyses and unsupervised learning algorithms defined deviations from normal that were designated "above threshold" and used to compute average nuclear abnormality of a second nuclear phenotype. RESULTS: Histologically normal epithelium from inclusion cysts of ovaries harboring a malignant lesion was shown to exhibit changes in the nuclear chromatin pattern that were statistically significant using quantitative image analysis procedures. Similar changes were seen in the inclusion cyst epithelia of high-risk ovaries. A subpopulation of cells representing a new phenotype was detected in the underlying stroma of women harboring a malignant ovarian lesion and in women at high risk of ovarian cancer. CONCLUSION: The karyometric changes observed in the epithelia lining inclusion cysts and in the underlying stroma of ovaries either with ovarian cancer or at high risk of ovarian cancer suggest the presence of preneoplastic changes in histologically normal tissue.

Cell Nucleus↗

Subvisual changes in chromatin organization state are detected by karyometry in the histologically normal urothelium in patients with synchronous papillary carcinoma.

This study analyzed the chromatin organization state in histologically normal urothelium in patients with synchronous papillary carcinoma using digital texture analysis. The quantitative evaluation was carried out on hematoxylin and eosin-stained sections from 17 cases of urothelial papillary carcinoma in which a simultaneous biopsy specimen featuring histologically normal urothelium was available. Five bladder biopsy specimens of histologically normal urothelium from patients with prostate pathology in whom cystoscopy revealed a normal bladder mucosa were also analyzed. Karyometry showed that the 17 cases of papillary carcinoma, morphologically classified according to the 1973 World Health Organization scheme, belonged to a continuous spectrum or trend curve spanning grade 1 to grade 3. An abnormal pattern and distribution of the nuclear chromatin was seen in the normal-looking urothelium from the 17 bladders with papillary lesions. When this population was plotted along the trend curve, it occupied an intermediate position between the normal samples and samples from grade 1 carcinoma. When the nuclei were considered individually, the changes were detected only in a subpopulation of nuclei with chromatin alteration pointing toward that seen in grade 1 cases, even though distinct from them. In conclusion, karyometry can detect an abnormal chromatin pattern and distribution in the normal-looking urothelium adjacent to papillary carcinoma. Such alterations correspond to the so-called "malignancy-associated change."

Carcinoma, Papillary↗

Malignancy-associated changes in lactiferous duct epithelium.

OBJECTIVE: To determine whether cells from histologically normal appearing epithelium of the lactiferous duct from women with a remote ductal lesion in the breast provide any clues indicating the existence of such a lesion. STUDY DESIGN: Tissue sections cut to 4 microns and stained with hematoxylin and eosin were prepared from duct tissue of 20 women with breast lesions and of 20 women free of any such lesion who had undergone mammoplastic procedures or resection for benign reasons. One hundred nuclei were measured from each case. Measures of nuclear deviation from normal were computed, discriminant functions were derived, and multivariate significance tests were conducted. RESULTS: Nuclei from histologically normal appearing regions of lactiferous duct epithelium from women harboring distant lesions exhibited changes in the distribution pattern of their nuclear chromatin, indicating the presence of these lesions. The statistical significance of these changes was documented. The changes were clearly evident in all 20 subjects with lesions and were not observed in 19 of the 20 subjects without lesions. CONCLUSION: The results suggest that studies aimed at detecting malignancy-associated changes in cells collected by ductal lavage might lead to a minimally invasive screening procedure for breast lesions.

Adult↗

A karyometric approach to the characterization of atypical endometrial hyperplasia with and without co-occurring adenocarcinoma.

OBJECTIVE: To develop a karyometric image analysis approach to distinguishing atypical endometrial hyperplasia with and without co-occurring adenocarcinoma. STUDY DESIGN: Six cases of atypical hyperplasia without and 6 cases with co-occurring adenocarcinoma, 4 cases of normal endometrium and 3 cases of adenocarcinoma were identified. From each case 100 nuclei were measured in representative diagnostic areas identified by an experienced pathologist. Discriminant analyses were performed. An unsupervised learning algorithm was applied to define and characterize different nuclear phenotypes, and those data were used to identify cases with co-occurring adenocarcinoma. RESULTS: Discriminant analysis showed that nuclei from atypical hyperplasia and atypical hyperplasia with co-occurring adenocarcinoma are statistically different. The unsupervised learning algorithm revealed differences in nuclear subpopulations that can be used to correctly identify an estimated 85% of individual cases. CONCLUSION: Nuclei from atypical hyperplasia without and with co-occurring adenocarcinoma have statistically different karyometric characteristics that may facilitate case classification.

Adenocarcinoma↗

A computer-based training system for breast fine needle aspiration cytology.

Fine-needle aspiration (FNA) cytology is a rapid and inexpensive technique used extensively in the diagnosis of breast disease. To remove diagnostic subjectivity, a diagnostic decision support system (DDSS) called CytoInform has been developed, based on a Bayesian belief network (BBN) for the diagnosis of breast FNAs. In addition to acting as a DDSS, the system implements a computer-based training (CBT) system, providing a novel approach to breast cytology training. The system guides the trainee cytopathologist through the diagnostic process, allowing the user to grade each diagnostic feature using a set of on-screen reference images as visual clues. The trainee positions a slider on a spectrum relative to these images, reflecting the similarity between the reference image and the microscope image. From this, an evidence vector is generated, allowing the current diagnostic probability to be updated by the BBN. As the trainee assesses each clue, the evidence entered is compared with that of the expert through the use of a defined teaching file. This file records the relative severity of each clue and a tolerance band within which the trainee must position the slider. When all clues in the teaching case have been completed, the system informs the user of inaccuracies and offers the ability to reassess problematic features. In trials with two pathologists of different experience and a series of ten cases, the system provided an effective tool in conveying diagnostic evidence and protocols to trainees. This is evident from the fact that each pathologist only misinterpreted one case and a total of 86%/88% (experienced/inexperienced) of all clues assessed were interpreted correctly. Significantly, in all cases that produced the correct final diagnostic probability, the route taken to that solution was consistent with the expert's solution.

Bayes Theorem↗