Number Of False-positive Results Research Articles

Genetic susceptibility to bladder cancer with an emphasis on gene–gene and gene–environmental interactions

The present article reviews recent reports on molecular epidemiological studies for exploring susceptibility genes for bladder cancer, with particular focus on gene-gene and gene-environmental interactions. Recent large case-control studies and meta-analyses have confirmed that N-acetyl transferase2 slow acetylator and glutathione S-transferase Mu null genotype were modest susceptibility factors for bladder cancer, with probable interactions between N-acetyl transferase2 slow acetylator and smoking. Several interesting studies using a multigenic pathway-based genotyping approach and novel statistical tools showed significant interactions among potential functional single nucleotide polymorphisms in DNA repair pathway genes and smoking and gene-diet interaction; however, the resultant interactions warrant validation. Previous studies using a candidate gene approach have not only identified a few bladder cancer susceptibility loci but also produced a large number of false positive results. A multigenic pathway-based approach may identify gene-gene and gene-environment interactions and increase predictive power. Several statistical tools have been applied to identify gene-gene and gene-environment interactions, but future efforts should be directed toward integrating results obtained from different statistical tools and validating resultant interactions from different studies.

Evaluation and use of the white blood cell differential provided by the Coulter STKS in a children's hospital.

The Coulter STKS was evaluated in a children's hospital, in order to (a) compare the WBC differential given by the instrument to a 400 cell visual differential (reference method); (b) evaluate the sensitivity and specificity of the alarm system, and (c) provide data concerning the use and interpretation of results in children. 653 blood samples were collected. The Coulter STKS results were studied in 523 patients having no morphological abnormalities in the blood smears, separated into subgroups according to the presence of STKS alarms and according to age. The results were found accurate both in STKS negative and STKS positive patients (i.e., those with alarms: 'Blasts', Imm Gran 2, Variant Lymph, NRBC, review slide). Negative STKS results had the same accuracy in all age groups, except in neonates where slide review must be systematically performed. The instrument exhibited a good sensitivity of the suspect flags studied (91.4%), with a lower specificity (72%) reflecting the number of false positive results found in our group, probably due to the cytological features particular to children. However, it was shown that the numerical results given by the Coulter STKS in positive patients could be taken into account, provided that a scan of the blood smear was negative for morphological WBC abnormalities.

Template bleeding time for preoperative screening in patients having orthognathic surgery

Excessive blood loss is a serious but rare complication of orthognathic surgery. The aim of this study was to find out whether template bleeding time (TBT) could detect primary bleeding disorders in patients having orthognathic operations and how many false positive tests there were. We also examined the correlation between the perioperative bleeding rate and the result of preoperative TBT. Patients who had orthognathic operations at Karolinska University Hospital, Huddinge, from August 2001 to December 2006, were screened preoperatively by measuring TBT and the records of their operations were reviewed retrospectively. Prolonged TBT was recorded in 20 patients (13%), 19 female and 1 male ( P = 0.02). After further examination, 10 of these patients were found to have a primary disorder of haemostasis. No detectable reason for the prolonged TBT could be found in the others. There was no significant difference in perioperative bleeding rate between patients with prolonged and normal TBT or between TBT and perioperative bleeding rate. In conclusion , the routine use of preoperative TBT for haemostatic screening in orthognathic surgery cannot be recommended because of the large number of false positive results. There was no significant correlation between prolonged TBT and bleeding during orthognathic surgery.

Technetium-99m hexamethyl propylene amine oxime-labeled leukocyte scintigraphy at three different times in active ulcerative colitis: comparison with colonoscopy and clinico-biochemical parameters in the assessment of disease extension and severity

In this study, our objective was to define the usefulness of technetium-99m hexamethyl propylene amine oxime (Tc-99m HMPAO)-labeled leukocyte scintigraphy at three different time points in the assessment of disease extension and severity in patients with active ulcerative colitis (UC). Twenty-one consecutive patients (10 women, 11 men; mean age 42.4 +/- 12 years) with active UC were prospectively studied. All patients were diagnosed by colonoscopy and histopathology prior to inclusion. Scintigraphy was performed at 1 h, 2 h, and 4 h after Tc-99m HMPAO-labeled leukocyte injection. Clinic-biochemical activity score, total colonoscopic activity score, and total scintigraphic activity score at 1 h, 2 h, and 4 h were calculated for each patient. Sensitivity, specificity, and accuracy values of Tc-99m HMPAO-labeled leukocyte scintigraphy were calculated as follows, respectively: 1 h imaging 86%, 73%, and 83%; 2 h imaging 89%, 74%, and 86%; 4 h imaging 90%, 58%, and 83% in the detection of active inflammatory segments. Even though no statistically significant difference was found between 1 h, 2 h, and 4 h imaging with respect to the sensitivity, specificity of labeled leukocyte scintigraphy, the largest area under the curve value was found for 2 h imaging. Tc-99m HMPAO-labeled leukocyte scintigraphy has been found to be correlated well with colonoscopy in the assessment of both the extension and severity of UC. We recommend 2 h scintigraphic imaging because it provides the largest area under the curve value and decreases the number of false-positive results.

The value of sonography in injuries of the knee joint

In an experimental study we examined three knee specimens with regard to the value of ultrasound for imaging soft tissue structures. Subsequently we documented artificial lesions at the menisci and ligaments. With this experience we started a prospective study comparing the preoperative ultrasound investigation with the results of arthroscopy in 101 patients. For ultrasound evaluation we used a 5 MHz linear and a 7.5 MHz sector scanner. In the experimental as well as in the clinical study the menisci were well visualised. For medial meniscus lesions the accuracy and the predictive value was 81%. For the lateral meniscus the predictive value was 80%, although there was only an accuracy of 7% because of a large number of false positive results. We were not able to reliably detect cruciate ligament ruptures. However, ultrasound was useful to visualise Baker's cysts, bursitis, and jumper's knee.

Improvement of the specificity of cancer detection by autofluorescence imaging in the tracheo-bronchial tree using backscattered violet light

Autofluorescence bronchoscopy (AFB) is a highly sensitive tool for the detection of early bronchial cancers. However, its specificity remains limited due to primarily false positive results induced by hyperplasia, metaplasia and inflammation. We have investigated the potential of blue-violet backscattered light to eliminate false positive results during AFB in a clinical pilot study. The diagnostic autofluorescence endoscopy (DAFE) system was equipped with a variable band pass filter in the imaging detection path. The backscattering properties of normal and abnormal bronchial mucosae were assessed by computing the contrast between the two tissue types for blue-violet wavelengths ranging between 410 and 490 nm in 12 patients undergoing routine DAFE examination. In a second study including 6 patients we used a variable long pass (LP) filter to determine the spectral design of the emission filter dedicated to the detection of this blue-violet light with the DAFE system. (Pre-)neoplastic mucosa showed a clear wavelength dependence of the backscattering properties of blue-violet light while the reflectivity of normal, metaplastic and hyperplastic autofluorescence positive mucosa was wavelength independent. Our results showed that the detection of blue-violet light has the potential to reduce the number of false positive results in AFB. In addition we determined the spectral design of the emission filter dedicated to the detection of this blue-violet light with the DAFE system.

Biolog identification of non-sorbitol fermenting bacteria isolated on <i>E. coli</i> O157 selective CT-SMAC agar

E. coli O157:H7 is recognised as an important human pathogen world-wide and has been associated with diseases such as haemorrhagic colitis (HC), haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP). Accurate laboratory detection of E. coli O157:H7 is important for diagnostic purposes and to justify epidemiological data on E. coli O157:H7. A well-known phenotypic characteristic of E. coli O157:H7 bacteria is their inability to ferment sorbitol. This characteristic is often used to isolate these organisms from food and water using selective agar medium such as SMAC. However, the high number of false positive results obtained by a number of researchers when selectively screening for E. coli O157: H7 on CT-SMAC has prompted an investigation to determine which other sorbitol-negative bacteria also grow on CT-SMAC. The agar medium used for the investigation consisted of Sorbitol MacConkey agar (SMAC) supplemented with Cefiximetellurite (CT). All sorbitol-negative colonies obtained from CT-SMAC, after selective enrichment and IMS were identified using the Biolog microbial identification system. The majority of sorbitol-negative isolates identified were Burkholderia, Pseudomonas, Vibrio and Aeromonas spp. Only two E. coli O157:H7 isolates were identified with Biolog and confirmed with a polymerase chain reaction (PCR) specific for the shiga toxin 1 (Stx1) genes and with O157 and H7 antisera. The inability of the CT-SMAC agar medium to specifically select for E.coli O157:H7 was confirmed by the results of this study. These observations call for further improvement of affordable methods for the selective isolation of E. coli O157:H7 in the presence of large numbers of interfering bacteria capable of growing on CT-SMAC. Water SA Vol. 31 (2) 2005: pp.247-252

A two-step multiple-marker strategy for genome-wide association studies

Genome-wide association studies raise study-design and analytical issues that are still being debated. Among them, stands the issue of reducing the number of markers to be genotyped without loss of efficiency in identifying trait loci, which can reduce the cost of studies and minimize the multiple testing problem. With this aim, we proposed a two-step strategy based on two analytical methods suited to examine sets of markers rather than single markers: the local score, which screens the genome to select candidate regions in Step 1, and FBAT-LC, a multiple-marker family-based association test used to obtain significance levels of regions at step 2. The performance of this strategy was evaluated on all replicates of Genetic Analysis Workshop 15 Problem 3 simulated data, using the answers to that problem. Overall, seven of the nine generated trait loci were detected in at least 87% of the replicates using a framework designed to handle either association with the disease or association with the severity of disease. This multiple-marker strategy was compared to the single-marker approach. By considering regions instead of single markers, this strategy minimizes the multiple testing problem and the number of false-positive results.

The diagnostic role of stress echocardiography in women with coronary artery disease: evidence based review

1) Coronary artery disease in women differs from men in several ways, including their response to many diagnostic tests.2) Strong comparative data on stress echocardiography for detecting coronary artery disease in women are lacking, but existing data consistently show sensitivity comparable with other high-sensitivity tests and superior specificity, increasing its diagnostic accuracy.3) Pharmacological stress echocardiography appears to provide superior specificity to exercise stress echocardiography due to difficulties in test execution with the latter that increase the number of false positive results.4) Current evidence suggests that stress echocardiography should be the first-line diagnostic tool for detecting coronary artery disease in women with chest pain, but other noninvasive imaging tests may be valuable in some patient subgroups.

Effect of simultaneous intracoronary guidewires on the predictive accuracy of functional parameters of coronary lesion severity

The aim of this study was to assess the influence of a second guidewire on the diagnostic accuracy of functional parameters of coronary lesion severity. Sixty-five patients with intermediate coronary lesions underwent myocardial perfusion scintigraphy. Fractional flow reserve (FFR), coronary flow velocity reserve (CFVR), and hyperemic stenosis resistance (HSR) index (HSR = stenosis pressure gradient / velocity) were determined in 77 lesions. Distal pressure and velocity were acquired simultaneously (dual wire) and sequentially (single wire) with two sensor-equipped guidewires. Overall, functional parameters deteriorated from single- to dual-wire assessment. In patients without ischemia, the good diagnostic performance of FFR, CFVR, and HSR deteriorated significantly (P < 0.001) when assessed by dual wires, with an increase in the number of false-positive results. This trend was more pronounced for HSR, since the presence of a second wire reduced maximal velocity and increased the pressure gradient. The presence of two guidewires, especially across a myocardial perfusion scintigraphy-induced nonsignificant lesion, is associated with overestimation of the hemodynamically assessed lesion severity and, therefore, is likely to have a major impact on clinical decision making. This underscores the advantage of a dual-sensor-equipped guidewire for the evaluation of stenosis severity by combined pressure and velocity measurements.

Shrunken p‐Values for Assessing Differential Expression with Applications to Genomic Data Analysis

In many scientific problems involving high-throughput technology, inference must be made involving several hundreds or thousands of hypotheses. Recent attention has focused on how to address the multiple testing issue; much focus has been devoted toward the use of the false discovery rate. In this article, we consider an alternative estimation procedure titled shrunken p-values for assessing differential expression (SPADE). The estimators are motivated by risk considerations from decision theory and lead to a completely new method for adjustment in the multiple testing problem. In addition, the decision-theoretic framework can be used to derive a decision rule for controlling the number of false positive results. Some theoretical results are outlined. The proposed methodology is illustrated using simulation studies and with application to data from a prostate cancer gene expression profiling study.

Differential diagnosis of solitary pulmonary nodules based on 99mTc-EDDA/HYNIC-TOC scintigraphy: the effect of tumour size on the optimal method of image assessment

The aim of the study was to determine an optimal method for the evaluation of scintigrams obtained with (99m)Tc-EDDA/HYNIC-TOC for the purpose of differential diagnosis of solitary pulmonary nodules (SPNs) and to assess the diagnostic value of the method. Eighty-five patients (48 males and 37 females, mean age 57 years, range 34-78 years) were enrolled in the study. Patients underwent (99m)Tc-EDDA/HYNIC-TOC scintigraphy for the purpose of differential diagnosis of SPNs (size between 1 and 4 cm). Images of all patients were evaluated visually in a prospective manner. Positive scintigraphic results were found in 37 out of 40 (93%) patients with malignant SPNs including 34 out of 35 (97%) patients with primary lung carcinoma. Two remaining false negative cases turned out to be metastatic lesions of malignant melanoma and leiomyosarcoma. Among 45 benign tumours, negative results were obtained in 31 cases (69%) and positive results in 14. The accuracy of the method was 80%. Analysis of the results of the visual assessment of scintigrams revealed a significantly higher frequency of false positive results among larger nodules (diameter at least 1.4 cm). Uptake of the tracer in those nodules was therefore assessed semi-quantitatively (using the tumour-to-background ratio), in expectation of an improvement in the low specificity of the visual method. The semi-quantitative assessment reduced the total number of false positive results in a subgroup of larger nodules from 13 to six, while preserving the high sensitivity of the method. The combination of visual analysis (for lesions smaller than 1.4 cm in diameter) and semi-quantitative assessment (for larger lesions) provided a high sensitivity of the method and significantly improved its specificity (84%) and accuracy (88%) in comparison with visual analysis (p<0.05).

Redefinition of the Q Wave—Is There a Clinical Problem?

This study evaluated the potential consequences of the redefined joint European/American electrocardiographic criteria for an established myocardial infarction (MI). New and previous diagnostic Q-wave criteria were used in patients with stable angina pectoris. Seventy-nine patients with and 77 patients without a documented previous MI were compared using the results of myocardial perfusion imaging at rest as a reference. With the new Q-wave criteria, 71% of the former group and 40% of the latter had evidence of established MI compared with 33% and 3% when using the previous criteria (p <0.0001). Sensitivity, specificity, and positive and negative predictive values were 71%, 60%, 64%, and 67% for the new criteria versus 33%, 97%, 93%, and 59% with the previous criteria. These data suggest that that the new Q-wave criteria may be too nonspecific, resulting in an inappropriately high number of false-positive results.

Quantitative determination of succinylacetone in dried blood spots for newborn screening of tyrosinemia type I

Background: Tyrosinemia type I (TYR 1) is a severe disorder causing early death if left untreated. While tyrosine can be determined in dried blood spots (DBS), it is not a specific marker for TYR 1 and most often associated with benign transient tyrosinemia of the newborn. Succinylacetone (SUAC) is a specific marker for TYR 1 but not detectable by routine newborn screening. We developed a new assay that determines SUAC in DBS by liquid-chromatography tandem mass spectrometry (LC–MS/MS). Methods: Whole blood is eluted from a 3/16-in. DBS by an aqueous solution containing deuterium labeled SUAC as internal standard (IS). SUAC and IS are oximated, then extracted, butylated, and analyzed by LC–MS/MS. Quantitation is from SUAC spiked calibrator DBS over the range 0–200 μM using selected reaction monitoring of transitions m/ z 212 to 156 and m/ z 214 to 140 for SUAC and IS, respectively. Analysis time is 5 min. To assess the effectiveness of a two-tier screening approach for TYR 1 we applied this assay to our newborn screening program over the last 15 months. Results: The intra-assay precision was determined for three different levels of SUAC (5, 20, and 50 μmol/L) and the CV calculated to be 4.7, 2.6, and 3.1%, respectively ( n = 5). Inter-assay precision CVs were 12.7, 8.2, and 7.8%, respectively on the same samples. SUAC levels in DBS from 10 confirmed TYR 1 cases not treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) were clearly abnormal (16–150 μmol/L; mean: 61 μmol/L; controls: <5 μmol/L). Over a 15-month period, SUAC was determined in newborn screening samples with elevated tyrosine concentrations when applying different cut off values until it was settled at 150 μmol/L. No case of TYR 1 was detected in 124,780 newborns tested. Conclusion: We have developed a new LC–MS/MS based method for the determination of SUAC in DBS. This assay has the potential to significantly reduce the number of false positive results in newborn screening for TYR 1 and can also be used for the laboratory follow up of patients treated for TYR 1.

Predicting the Strongest Domain-Domain Contact in Interacting Protein Pairs

Experiments to determine the complete 3-dimensional structures of protein complexes are difficult to perform and only a limited range of such structures are available. In contrast, large-scale screening experiments have identified thousands of pairwise interactions between proteins, but such experiments do not produce explicit structural information. In addition, the data produced by these high through-put experiments contain large numbers of false positive results, and can be biased against detection of certain types of interaction. Several methods exist that analyse such pairwise interaction data in terms of the constituent domains within proteins, scoring pairs of domain superfamilies according to their propensity to interact. These scores can be used to predict the strongest domain-domain contact (the contact with the largest surface area) between interacting proteins for which the domain-level structures of the individual proteins are known. We test this predictive approach on a set of pairwise protein interactions taken from the Protein Quaternary Structure (PQS) database for which the true domain-domain contacts are known.While the overall prediction success rate across the whole test data set is poor, we shown how interactions in the test data set for which the training data are not informative can be automatically excluded from the prediction process, giving improved prediction success rates at the expense of restricted coverage of the test data.

Plasma levels of tumor M2-pyruvate kinase should not be used as a tumor marker for hematological malignancies and solid tumors

It has been reported that the dimeric isoform of the enzyme pyruvate kinase M2 was overexpressed in various solid tumor cells. Hence, it was suggested that circulating levels of the so-called tumor M2-pyruvate kinase (Tu M2-PK) could be used as a tumor marker for monitoring systemic therapies of various solid tumors. We analyzed its validity as a tumor marker by comparing plasma levels of Tu M2-PK in patients with different non-malignant diseases to levels in healthy individuals and in patients with hematological diseases. Plasma levels of Tu M2-PK were measured using an ELISA assay in a total of 284 patients. The mean Tu M2-PK concentration of 32 U/mL was significantly higher in the group of patients with hematological malignancies (n = 121) (p < 0.001). However, 37% of healthy individuals (n = 63) and 44% of patients with non-malignant diseases (n = 100), especially patients with an acute inflammatory reaction (67%), were found to have elevated levels of Tu M2-PK using a cutoff level of 15 U/mL. The specificity was 59% and the sensitivity was 51%. There was no significant correlation between the prevalence of a hematological malignancy and positive Tu M2-PK result. Thus, our data imply that Tu M2-PK is not a useful tumor marker for hematological malignancies and solid tumors, as a significant number of false positive results were detected in healthy individuals and patients with non-malignant diseases.

Assessment of the biliary tract after liver transplantation: T tube cholangiography or IODIDA scanning

Biliary tract obstruction or anastomotic leakage are common problems following liver transplantation. In a sequential study, 31 patients with a liver transplant were investigated by 99mTc-IODIDA (IODIDA) scanning and T tube cholangiography (TTC) and the results were compared with clinical outcome. Seven patients had an extrahepatic biliary obstruction and one patient had a biliary leak. In the detection of biliary complications TTC and IODIDA scanning were similar in terms of sensitivity (63 per cent for both) but TTC had a better specificity (79 per cent versus 60 per cent) and accuracy (74 per cent versus 60 per cent) than IODIDA scanning. When liver function was taken into account, the diagnostic efficacy of both tests in patients with bilirubin levels of less than 200 mumol/l was similar. With levels greater than 200 mumol/l there was a greater number of false positive results with IODIDA scanning (12 per cent versus 54 per cent). The only significant biliary leak was clearly detected by TTC but not IODIDA scanning. TTC remains the more effective way of evaluating the biliary tract after transplantation. IODIDA scanning has limited value when bilirubin levels are elevated, but may provide additional information about blood supply, hepatocyte function and intrahepatic cholestasis.

Investigation of altering single-nucleotide polymorphism density on the power to detect trait loci and frequency of false positive in nonparametric linkage analyses of qualitative traits

Genome-wide linkage analysis using microsatellite markers has been successful in the identification of numerous Mendelian and complex disease loci. The recent availability of high-density single-nucleotide polymorphism (SNP) maps provides a potentially more powerful option. Using the simulated and Collaborative Study on the Genetics of Alcoholism (COGA) datasets from the Genetics Analysis Workshop 14 (GAW14), we examined how altering the density of SNP marker sets impacted the overall information content, the power to detect trait loci, and the number of false positive results. For the simulated data we used SNP maps with density of 0.3 cM, 1 cM, 2 cM, and 3 cM. For the COGA data we combined the marker sets from Illumina and Affymetrix to create a map with average density of 0.25 cM and then, using a sub-sample of these markers, created maps with density of 0.3 cM, 0.6 cM, 1 cM, 2 cM, and 3 cM. For each marker set, multipoint linkage analysis using MERLIN was performed for both dominant and recessive traits derived from marker loci. Our results showed that information content increased with increased map density. For the homogeneous, completely penetrant traits we created, there was only a modest difference in ability to detect trait loci. Additionally, as map density increased there was only a slight increase in the number of false positive results when there was linkage disequilibrium (LD) between markers. The presence of LD between markers may have led to an increased number of false positive regions but no clear relationship between regions of high LD and locations of false positive linkage signals was observed.

Sensibilidad de los rebaños en relación con la sensibilidad de las pruebas serológicas para la enfermedad vesicular porcina

After the swine vesicular disease (SVD) outbreaks in 1992 in the Netherlands a national monitoring programme was initiated, testing 12 samples from every pig farm three times per year. In this monitoring a slightly higher cut-off was used than the cut-off agreed on within the European community. The author has analysed the effect of this higher cut-off on the percentage of false positive and false negative results, using information on SVD antibody titres in sera obtained from the monitoring programme and the outbreaks in 1992 and 1994. The number of false positive results was reduced by 63% when using the higher cut-off. On average the test sensitivity was reduced from 100% to 88%, resulting in a change of the average herd sensitivity from 91.7% to 91.5%, when testing 12 samples per farm. When three samples per farm were tested, the average herd sensitivity changed from 64.9% to 62.9%. The results further indicate that, in contrast to what is generally presumed, there is a relationship between test sensitivity and the prevalence of infection. The results clearly show that sample size is far more important in obtaining a high herd sensitivity than achieving a high test sensitivity.

3. Is exercise good for you?

Physical activity can significantly reduce the risk of cardiovascular disease, diabetes, some forms of cancer, osteoporosis, obesity, falls and fractures, and some mental health problems. While the benefits of physical activity are clear, there is a slightly increased risk of sudden death while exercising (compared with while sedentary), especially in untrained people undertaking unaccustomed vigorous activity. Routine exercise testing yields a significant number of false-positive results, and has not been shown to prevent exercise-related acute cardiac events. There is no convincing evidence that exercise is itself associated with osteoarthritis, but significant joint injury which occurs during sport is associated with an increased risk of subsequent development of osteoarthritis.