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Model selection for a medical diagnostic decision support system: a breast cancer detection case.

There are a number of different quantitative models that can be used in a medical diagnostic decision support system (MDSS) including parametric methods (linear discriminant analysis or logistic regression), non-parametric models (K nearest neighbor, or kernel density) and several neural network models. The complexity of the diagnostic task is thought to be one of the prime determinants of model selection. Unfortunately, there is no theory available to guide model selection. Practitioners are left to either choose a favorite model or to test a small subset using cross validation methods. This paper illustrates the use of a self-organizing map (SOM) to guide model selection for a breast cancer MDSS. The topological ordering properties of the SOM are used to define targets for an ideal accuracy level similar to a Bayes optimal level. These targets can then be used in model selection, variable reduction, parameter determination, and to assess the adequacy of the clinical measurement system. These ideas are applied to a successful model selection for a real-world breast cancer database. Diagnostic accuracy results are reported for individual models, for ensembles of neural networks, and for stacked predictors.

Algorithms↗

Osteopontin as a potential diagnostic biomarker for ovarian cancer.

CONTEXT: Development of new biomarkers for ovarian cancer is needed for early detection and disease monitoring. Analyses involving complementary DNA (cDNA) microarray data can be used to identify up-regulated genes in cancer cells, whose products may then be further validated as potential biomarkers. OBJECTIVE: To describe validation studies of an up-regulated gene known as osteopontin, previously identified using a cDNA microarray system. DESIGN, SETTING, AND PARTICIPANTS: Experimental and cross-sectional studies were conducted involving ovarian cancer and healthy human ovarian surface epithelial cell lines and cultures, archival paraffin-embedded ovarian tissue collected between June 1992 and June 2001, and fresh tissue and preoperative plasma from 144 patients evaluated for a pelvic mass between June 1992 and June 2001 in gynecologic oncology services at 2 US academic institutions. Plasma samples from 107 women selected from an epidemiologic study of ovarian cancer initiated between May 1992 and March 1997 were used as healthy controls. MAIN OUTCOME MEASURES: Relative messenger RNA expression in cancer cells and fresh ovarian tissue, measured by real-time polymerase chain reaction as 2(-DeltaDeltaCT)(a quantitative value representing the amount of osteopontin expression); osteopontin production, localized and scored in ovarian healthy and tumor tissue with immunohistochemical studies; and amount of osteopontin in patient vs control plasma, measured using an enzyme-linked immunoassay. RESULTS: The geometric mean for 2(-DeltaDeltaCT)for osteopontin expression in 5 healthy ovarian epithelial cell cultures was 4.1 compared with 270.4 in 14 ovarian cancer cell lines (P =.03). The geometric mean 2(-DeltaDeltaCT)for osteopontin expression in tissue from 2 healthy ovarian epithelial samples was 9.0 compared with 164.0 in 27 microdissected ovarian tumor tissue samples (P =.06). Immunolocalization of osteopontin showed that tissue samples from 61 patients with invasive ovarian cancer and 29 patients with borderline ovarian tumors expressed higher levels of osteopontin than tissue samples from 6 patients with benign tumors and samples of healthy ovarian epithelium from 3 patients (P =.03). Osteopontin levels in plasma were significantly higher (P<.001) in 51 patients with epithelial ovarian cancer (486.5 ng/mL) compared with those of 107 healthy controls (147.1 ng/mL), 46 patients with benign ovarian disease (254.4 ng/mL), and 47 patients with other gynecologic cancers (260.9 ng/mL). CONCLUSIONS: Our findings provide evidence for an association between levels of a biomarker, osteopontin, and ovarian cancer and suggest that future research assessing its clinical usefulness would be worthwhile.

Biomarkers, Tumor↗

Diagnostic accuracy of colorectal cancer staging with whole-body PET/CT colonography.

CONTEXT: Staging of patients with colorectal cancer often requires a multimodality, multistep imaging approach. Colonography composed of a combined modality of positron emission tomography (PET) and computed tomography (CT) provides whole-body tumor staging in a single session. OBJECTIVES: To determine the staging accuracy of whole-body PET/CT colonography compared with the staging accuracies of CT followed by PET (CT + PET) and CT alone and to evaluate the effect of PET/CT colonography on therapy planning compared with conventional staging (CT of the abdomen and thorax and optical colonoscopy). DESIGN, SETTING, AND PATIENTS: Prospective study of 47 patients enrolled between May 2004 and June 2006 with clinical findings and optical colonoscopy that suggested primary colorectal cancer (mean [SD] age, 71 [11] years; range, 47-92 years). Patients underwent whole-body PET/CT colonography 1 day after colonoscopy. The study was conducted at a university hospital with a mean (SD) follow-up of 447 (140) days (range, 232-653 days). MAIN OUTCOME MEASURES: Correct classification of overall TNM stage using PET/CT colonography compared with CT + PET and CT alone. Secondary outcome measures were the accurate assessment of T-stage, N-stage, and M-stage by PET/CT colonography compared with CT + PET and CT alone and the effect of PET/CT colonography on therapy planning. RESULTS: Of the 47 patients with a total of 50 lesions, the overall TNM stage was correctly determined for 37 lesions with PET/CT colonography (74%; 95% confidence interval [CI], 60%-85%), 32 lesions with CT + PET (64%; 95% CI, 49%-77%), and 26 lesions with CT alone with a 0.7-cm node threshold (52%; 95% CI, 37%-66%). Compared with optimized abdominal CT staging alone, PET/CT colonography was significantly more accurate in defining TNM stage (difference, 22%; 95% CI, 9%-36%; P=.003), which was mainly based on a more accurate definition of the T-stage. Differences were not detected for defining N-stage between PET/CT colonography and CT alone with a threshold of 0.7 cm for malignant nodes but were detected with a threshold of 1 cm. Differences were not detected in defining M-stage separately or when comparing the accuracies of PET/CT colonography with CT + PET. PET/CT colonography affected consecutive therapy decisions in 4 patients (9%; 95% CI, 2.4%-20.4%) compared with conventional staging (CT alone and colonoscopy). CONCLUSIONS: In this preliminary study, PET/CT colonography is at least equivalent to CT + PET for tumor staging in patients with colorectal cancer. Thus, PET/CT colonography in conjunction with optical colonoscopy may be a suitable concept of tumor staging for patients with colorectal cancer.

Aged↗

Morphologic pattern of tenascin as a diagnostic biomarker in colon cancer.

BACKGROUND: Immunohistochemical methods were used to study the pattern of expression of tenascin (TN) in invasive colon cancer and its relation to prognosis. METHODS: Sixty patients (29 males, 31 females) with a mean age of 77 years were studied. TN expression was evaluated by immunohistochemistry using paraffin-embedded tissue sections, TN expression levels were correlated with patient age, tumor stage, and survival. RESULTS: TN positivity varied from trace to 4+. Staining patterns were as follows: in well-differentiated cancer, TN fibers form thick bands around invading tumor glands. In poorly differentiated cancer, TN fibers had an interstitial pattern surrounding individual tumor cells. Using Cox's proportional hazard regression method, survival was significantly related to TN score (P < 0.0001) and stage of disease (P < 0.05). No significant relationship was found between survival and age (P = 0.375). CONCLUSION: Patients with more TN expression had better long-term survival than patients with no or weak TN expression. Pathologic and clinical entities in colon cancer have distinct immunohistochemical TN matrix patterns that may correlate with predictive value and long-term survival.

Adenocarcinoma↗

Analysis of numerical aberrations of specific chromosomes by fluorescent in situ hybridization as a diagnostic tool in breast cancer.

BACKGROUND: Biopsy by fine-needle, aspiration has become a routine technique for the diagnosis of a dominant breast mass. In this study, fluorescent in situ, hybridization (FISH) analysis of interphase nuclei allowed the authors to detect genetic aberrations that are difficult to identify by conventional cytology. METHODS: To investigate ways of minimizing misdiagnosis of the cytology of breast tumors, and detecting genetic aberrations preoperatively, the authors performed FISH with specimens obtained by fine-needle aspiration biopsies of 106 primary breast tumors (78 primary breast cancers, 2 phyllodes tumors, and 26 benign breast tumors). Numerical chromosome aberrations were investigated using 3-color FISH performed with (peri)centromere-specific probes for chromosomes 1, 11, and 17. RESULTS: Sufficient materials for FISH analysis were obtained with aspiration biopsy from 98 of the 106 breast tumors (93.4%). None of the benign tumors nor phyllodes tumors showed evidence of aneusomy for any of the 3 chromosomes. However, 71 of the 74 breast cancers (95.9%) for which sufficient material was available demonstrated aneusomy of at least 1 of the 3 chromosomes tested. The FISH analysis also suggested a possible correlation between aneusomy of chromosome 17 and metastasis to regional lymph nodes (chi-square test = 7.78; P < 0.05). CONCLUSIONS: FISH analysis of fine-needle aspiration biopsies can be a practical and useful method for the preoperative diagnosis of breast carcinoma.

Biopsy, Needle↗

Improved diagnostic accuracy in laryngeal cancer using a new classification based on computed tomography.

The most commonly accepted classification of laryngeal cancer is based on the definition of regions formulated by the American Joint Committee on Laryngeal Cancer. The limitations of this classification are discussed. A new radiologic classification based on computed tomography (CT) is presented, its application illustrated, and its accuracy documented. This classification has the advantage that it provides information preoperatively which closely agrees with the pathologic facts seen postoperatively. It also helps to separate those tumors that tend to invade cartilage from those that do not.

Biopsy↗

Diagnostic delay in breast cancer.

BACKGROUND: Delay in the diagnosis of breast cancer has important clinical and medicolegal implications. This study assessed the frequency, causes and effects of delay in the diagnosis of breast cancer in a specialist breast unit. METHODS: Details of women who attended the breast clinic between 1988 and 1999 inclusive, and for whom the interval between first attendance and diagnosis of invasive breast cancer was greater than 2 months, were reviewed. Potential causes of delay were identified and the consequence of the delay assessed. The clinical features were compared with those of patients diagnosed with breast cancer during a 2-year period from 1999 and 2001. RESULTS: Breast cancer was diagnosed in 5283 women during the interval reviewed; delay in diagnosis was suggested in 72 women (1.4 per cent). Women with a delayed diagnosis were younger (P < 0.001) and had a smaller tumour at diagnosis (P = 0.011) compared with all women diagnosed with breast cancer between 1999 and 2001. There were no differences in the rate of axillary node positivity or the need for mastectomy. Women unsuitable for conservation therapy in the delayed group had a significantly longer interval to diagnosis (P = 0.006). CONCLUSION: The likelihood that conservation therapy will be appropriate is reduced when the hospital delay in the diagnosis of breast cancer is more than 240 days. All patients with a palpable mass require triple assessment to minimize delay in diagnosis of breast cancer.

Adult↗

Expression analysis of delta-catenin and prostate-specific membrane antigen: their potential as diagnostic markers for prostate cancer.

The current approach to prostate cancer diagnosis has major limitations including the inability of prostate-specific antigen (PSA) assays to accurately differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the imprecision of transrectal ultrasound (TRUS) biopsy sampling. We have employed cDNA microarray screening to compare gene expression patterns in BPH and tumour samples to identify expression markers that may be useful in discriminating between these conditions. Screening of 3 individual cDNA arrays identified 8 genes with expression 3-fold greater in 6 tumour tissues than in 1 nontumour sample and 1 BPH sample. Real-time PCR was used to confirm the overexpression of these 8 genes and 12 genes selected from the literature against a panel of 17 tumours and 11 BPH samples. Two genes, delta-catenin (delta-catenin; CTNND2) and prostate-specific membrane antigen (PSMA; FOLH1), were significantly overexpressed in prostate cancer compared to BPH. Prostate epithelial cells stained positively for delta-catenin and PSMA in our prostate cancer tissues, whereas the majority of our BPH tissues were negative for both markers. Thus we have identified delta-catenin (not previously associated with prostatic adenocarcinoma) and confirmed the potential of PSMA as potential candidates for the diagnosis and management of prostate cancer.

Adult↗

Diagnostic ultrasound in breast cancer: analysis of retrotumorous echo patterns correlated with sonic attenuation by cancerous connective tissue.

Echocardiographic diagnosis of breast cancer has been used in clinical medicine for the past several years. Echographic findings and characteristics suggesting differentiation between malignant and benign tumors have been reported by various investigators. These signs are analysed in correlation with histological findings, especially cancerous connective tissue and nonconnective tissue and retrotumorous shadow patterns in clinical echograms of various breast cancers. Special reference is made to ultrasound attenuation related to bioacoustical tissue characteristics. This casual mechanism provides a stepping-stone for further improvements in ultrasound apparatus designed for clinical diagnosis of breast cancer. Furthermore, it may stimulate basic research on the bioacoustical properties of ultrasound reflection, absorption, and velocity.

Adenocarcinoma, Scirrhous↗

Diagnostic studies of thyroid cancer.

Patient with goiter usually has benign disease. While investigation is important, clinical factors weight heavily in the diagnosis of cancer. Aside from serum calcitonin and CEA, biochemical findings are of little help. Radioisotope scanning is of fundamental importance and has an implication in history. Ultrasonography has a diminishing role although its use has led to the widespread acceptance of needle aspiration. Needle aspiration cytology is now the most important maneuver in preoperative assessment and management of the goiter patient. Its results permit refined operative selection, the institution of safe conservative management, and greater organization in surgical treatment. Persistent cooperation between clinician and pathologist can yield a high rate of the reliable preoperative cytological diagnosis obtained by needle aspiration.

Biopsy, Needle↗

Diagnostic markers of prostate cancer: utility of prostate-specific antigen in diagnosis and staging.

The optimal tumor marker for prostate cancer would be effective for early detection, staging, and monitoring patients after definitive treatment. This marker would have a high sensitivity, specificity, and positive predictive value for distinguishing men with benign prostatic hyperplasia (BPH) from men with early prostate cancer. Such a marker would consistently detect biologically significant disease, correlate with clinical and pathologic staging, and predict prognosis. In addition, this marker would be accurate at indicating cure or progression of disease after treatment. Certainly, the ideal marker also would be reproducible, inexpensive, generate results rapidly, be easy to perform, be accessible to clinicians, and tolerable to patients. Unfortunately, such a "super" marker does not exist at this time. However, prostate-specific antigen (PSA) has many of the aforementioned capabilities. This article will describe the current utility of PSA in the diagnosis and staging of prostate cancer.

Acid Phosphatase↗

Protein tyrosine phosphatase activity as a diagnostic parameter in breast cancer.

Cellular phosphotyrosine levels are regulated by the balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). It is supposed that this balance is disturbed in tumour cells, making the increased or altered activity of PTKs and PTPs likely hallmarks of tumour tissues. Indeed it could be shown that the PTK activity was increased in breast cancer in correlation with prognosis (Hennipman et al., Cancer Res. 49, 516-522, 1989). In the present report we measured the PTP activities in breast cancer and normal breast tissues. An increase of approximately three- to four-fold was measured in the cytosolic tumour fractions compared to normal, whereas the solubilized membrane fraction PTP activity showed an increase in tumours of approximately 1.5-fold. Remarkably, the membrane PTP activity correlated with the presence of tumour positive axillary lymph nodes (p = 0.004), whereas the cytosolic PTP activity correlated with the mitotic index, a higher PTP activity occurring when the mitotic index was higher than 10 (p = 0.0004). These results indicate the membrane PTP activity may be considered as an index of metastatic potential, whereas cytosolic PTP activity may be a measure of the growth capacity of the tumour. The increase of PTP activity in breast cancers was confirmed by enzyme-histochemical studies. In frozen sections of tumours a strong to moderate activity was found in both tumour cells and interstitial cells. In the interstitium membrane activity was most pronounced, whereas in the tumour cells diffuse staining of the cytoplasm together with a clear membrane staining was demonstrated. Immunoblotting with anti-phosphotyrosine antibodies also reveals differences between the tumours and normal tissues, confirming the disturbance of the balance between protein tyrosyl phosphorylation and dephosphorylation in the tumour cells.

Breast↗

New diagnostic imaging in rectal cancer: endosonography and immunoscintigraphy.

Endosonography of the rectum, combining the advantages of both endoscopy and sonography, provides information not at present available from other imaging modalities. It is remarkably accurate in the pre-operative assessment of tumor penetration. In the evaluation of lymph nodes, the specificity and sensitivity is 83% and 72%, respectively. For the detection of local recurrence in asymptomatic patients promising results can be obtained. In contrast, the potential benefits of immunoscintigraphy in patients with rectal cancer have yet to be determined but preliminary results indicate that immunoscintigraphy in combination with endosonography may assist the surgeon in confirming or excluding the suspicion of recurrence.

Endoscopes, Gastrointestinal↗