Proportion Of False-positive Results Research Articles

Abstract PO2-29-03: Factors Affecting the Mammography Sensitivity and the Quality of the Breast Cancer Screening Program in the State of São Paulo, Brazil

Abstract Background: Previous researches found that false-positive mammogram results during breast cancer screening are related to age, family history of breast cancer, body mass index, and breast density. In Brazil, there is limited data available on possible factors that may influence the sensitivity of mammography and, consequently, the overall quality of the breast cancer screening program. Aims: This study aims to conduct a sensitivity analysis comparing the results of screening mammograms with diagnosis of breast cancer, taking into account factors that could impact this sensitivity. Methods: All mammogram and biopsy results in the state of São Paulo in 2013 were obtained from the Brazilian Breast Cancer Information System (SISMAMA) database. We obtained information on age (< 50, 50-59, 60-69, or 70+ years), type of lesion (solid, cyst, or calcifications), lesion size (< 10mm, 11-20mm, 21-50mm, or >50mm), lesion boundaries (defined or undefined), lesion characteristics (regular or irregular), and breast density (fatty/predominant fatty or dense/predominant dense). In addition, we evaluated the hormonal therapy usage (yes or no), radiotherapy treatment (yes or no), ethnicity (caucasian, asian, or black), education (illiterate, completed elementary school, completed high school, or completed higher education), skin type (retracted, thickened, or normal), and type of mammogram (simple or computerized). Our analysis focused on mammograms classified as BI-RADS 4, BI-RADS 5, and those with inconclusive results, which subsequently led to a biopsy for diagnosis. We conduct statistical analysis using SPSS v.29 software. To assess the agreement between mammograms and biopsy results (sensitivity), we calculated the proportion of true positive results. We compared the sensitivity across different strata of variables using the Chi-Square test and the V-Cramer measure. Results: A total of 6,064 women with BI-RADS 4, BI-RADS 5, or inconclusive mammogram results underwent biopsy procedures for breast cancer diagnosis. Among these cases, 3,414 (56.3%) were false positives, 1,765 (29.1%) were true positives, and 885 (14.6%) were inconclusive results. The sensitivity of mammographic screening was not significantly associated with ethnicity, education, type of mammogram, skin type, or previous radiotherapy. However, a higher proportion of false positive results was linked to high breast density (71.2%), irregular lesions with defined boundaries (87.5%), particularly calcifications (68.7%) smaller than 10 mm (67.5 %). True positive results, on the other hand, were associated with solid (87.1%) and irregular lesions with undefined boundaries (82.1 %), often larger than 50 mm (57.2%) in fatty breasts (82.7%). A notable proportion of inconclusive results was associated with the presence of dense/predominant dense breasts (88.4%) and irregular lesions with undefined boundaries (87%), particularly solid lesions (89.8%) ranging from 21 to 50 mm in size (60.8%). False positive and inconclusive results were more prevalent among women under 50 years old (79.8%) and those using hormonal therapy (54.8%) compared to true positives. This study has certain limitations, including the availability of data related to lesion density and morphology, as well as body mass index in the SISMAMA database, all of which can potentially impact mammography sensitivity. Furthermore, a notable limitation was a substantial number of missing values for ethnicity and education in the SISMAMA dataset. Conclusion: We identified associations between false-positive and inconclusive results on screening mammograms and factors such as age, breast density, lesion size, lesion types, and hormonal therapy. These results provide valuable information about potential factors that may affect the accuracy of mammography interpretations. Therefore, they must be taken into consideration when planning a breast cancer screening program. Citation Format: Alice Câmara, Lise Cury, Victor Filho. Factors Affecting the Mammography Sensitivity and the Quality of the Breast Cancer Screening Program in the State of São Paulo, Brazil [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-29-03.

Comparing the Indices predictive of the thermal injury outcome

Introduction. While developing the algorithms for diagnosis and treatment of patients with thermal injury, an injury outcome prediction index with the best predictive properties should be used.Aim. To compare the predictive properties of the Revised Frank Index and other specialized indices.Material and methods. A retrospective observational study included 307 patients with thermal injury, of whom 80 (26%) died. We compared the discriminatory ability, as well as sensitivity, specificity, positive predictive value and negative predictive value, the accuracy of the diagnostic test in relation to predicting a fatal outcome for 8 specialized prediction indices: RFI, FI, Baux, RBS, PBI, ABSI, BOBI, and Ryan.Results. RFI showed the largest area under the ROC curve: 0.942 [0.913–0.971], other indices had a smaller area: FI 0.827 [0.768–0.886], Baux 0.860 [0.811–0.909], RBS 0.891 [0.848–0.933], PBI 0.893 [0.848–0.937], ABSI 0.838 [0.786–0.890], BOBI 0.865 [0.819–0.910], Ryan 0.816 [0.764–0.869]. The Ryan index had the highest sensitivity (95%), but its specificity (49%) was the lowest, and the proportion of false positive results was 60%. The RBS index had high sensitivity (84%) and specificity (80%), but the false positive rate was 40%. The RFI and PBI indices showed similar sensitivity (81%), however, the proportion of false positive results for RFI (23%) was lower than that of PBI (39%) and all other indices, and the RFI accuracy in predicting the outcome was the highest among the other indices, making 89%.Conclusion. The predictive properties of the Revised Frank Index are better than those of other specialized indices.

Clinical performance study of a fecal bacterial signature test for colorectal cancer screening.

The fecal immunochemical test (FIT) is the most widely used test for colorectal cancer (CRC) screening. RAID-CRC Screen is a new non-invasive test based on fecal bacterial markers, developed to complement FIT by increasing its specificity. The test was previously clinically evaluated in FIT-positive patients (>20 μg of hemoglobin/g of feces, "FIT20"), in which it reduced the proportion of false positive results by 16.3% while maintaining most of FIT20's sensitivity. The aim of this study was to compare the sensitivity and specificity of a CRC screening program using RAID-CRC Screen in addition to FIT20 as a triage test in a European screening population undergoing screening colonoscopy with a CRC screening program with FIT20 alone in the same cohort. A cohort of 2481 subjects aged > 55 years from the German screening colonoscopy program was included. The colonoscopy findings were used as the gold standard in calculating the diagnostic capacity of the tests and included 15 CRC and 257 advanced neoplasia cases. RAID-CRC Screen added to FIT20 provided the same sensitivity as FIT20 alone (66.7%) in detecting CRC and a significantly higher specificity (97.0% vs. 96.1%, p<0.0001). The positive predictive value was 11.9% when using RAID-CRC Screen and 9.5% with FIT20 alone, and the negative predictive value was 99.8% in the two scenarios. For advanced neoplasia detection, the use of RAID-CRC Screen yielded significantly lower sensitivity than with FIT20 alone (17.5% vs. 21.8%, p = 0.0009), and the overall specificity was significantly higher when using RAID-CRC Screen compared with FIT20 alone (98.2% vs. 97.8%, p = 0.0039). Our findings confirm the results obtained in previous clinical studies in a CRC screening setting, showing the potential of RAID-CRC Screen to increase the overall specificity of FIT-based screening.

A novel three-biomarker signature (CA-62, CEA, CYFRA 21-1) and early-stage NSC lung cancer detection.

3038 Background: A double-blind clinical study was conducted on 304 clinically verified blood serum samples, including 141 non-small cell lung cancer (NSCLC), 133 healthy volunteers and 30 patients with chronic obstructive pulmonary disease (COPD). The objectives of the study were: The assessment of various cancer markers and their possible combinations for detection of early (I-II) stages of non-small cell lung cancer (NSCLC) and evaluation of the best cancer markers panel as a pre-screening tool for NSCLC before Low-Dose CT scan. Methods: Quantitative measurement of various tumor markers for serum samples was carried out using electrochemiluminescent immunoassays Elecsys CA-125, ELECSYS CA 19-9, ELECSYS CYFRA 21-1 and ELECSYS SCC (COBAS, Roche Diagnostics GmbH, Germany, EU), enzyme immunoassay CA15-3-ELISA-BEST, CEA-ELISA-BEST, NSE-ELISA-BEST (JSC "VECTOR-BEST", RF) and immunochemiluminescent analysis CLIA-CA-62 (LLC "JVS Diagnostics", RF). The results were compared to the literature data for other biomarkers and their panels. Results: Unlike other tumor markers, which are expressed proportionally to tumor size, the marker for epithelial carcinomas CA-62 is expressed from Stage I and demonstrated the highest diagnostic results in detecting early stages (I-II) of NSCLC. The biomarkers CYFRA 21-1 and SCC do not have sufficient sensitivity and specificity to diagnose asymptomatic lung cancer. However, the addition of cytokeratin 19 CYFRA 21-1 to glycoproteins CA-62 and CEA increases the specificity by eliminating false positive results, which significantly improves the diagnostic value of the cancer marker signature (CA-62, CEA and CYFRA 21-1): 100% Specificity, 93% Sensitivity, 100% PPV, 94% NPV and 94% test accuracy. Conclusions: The results of the study demonstrated that using the biomarkers signature (CA-62, CEA and CYFRA 21-1) allows increasing the specificity of CT scan for patients with suspicious abnormalities on the tomogram, improving the interpretation of visualized localized lesion, and improving the accuracy of differential diagnosis at detecting early stages of LC up to 94%. In the prospective, adding cancer markers panel signature (CA-62, CEA and CYFRA 21-1) to the current lung cancer risk assessment system as a pre-screening tool for LDCT may improve the quality of early-stage Lung cancer detection by significant increasing the sensitivity and by reducing the proportion of false positive results. [Table: see text]

Contamination of Blood Cultures From Arterial Catheters and Peripheral Venipuncture in Critically Ill Patients: A Prospective Multicenter Diagnostic Study

Collecting blood cultures from indwelling arterial catheters is an attractive option in critically ill adult patients when peripheral venipuncture is difficult. However, whether the contamination proportion of blood cultures from arterial catheters is acceptable compared with that from venipuncture is inconclusive. Is contamination of blood cultures from arterial catheters noninferior to that from venipuncture in critically ill adult patients with suspected bloodstream infection? In this multicenter prospective diagnostic study conducted at five hospitals,we enrolled episodes of paired blood culture collection, each set consisting of blood drawn from an arterial catheter and another by venipuncture, were obtained from critically ill adult patients with cilinical indication. The primary measure was the proportion of contamination, defined as the number of false-positive results relative to the total number of procedures done. The reference standard for true bloodstream infection was blinded assessment by infectious disease specialists. We examined the noninferiority hypothesis that the contamination proportion of blood cultures from arterial catheters did not exceed that from venipuncture by 2.0%. Of 1,655 episodes of blood culture from December 2018 to July 2021, 590 paired blood cultureepisodes were enrolled, and 41 of the 590 episodes (6.9%) produced a true bloodstream infection. In blood cultures from arterial catheters, 33 of 590 (6.0%) were positive, and two of 590 (0.3%) were contaminated; in venipuncture, 36 of 590 (6.1%) were positive, and four of 590 (0.7%) were contaminated. The estimated difference in contamination proportion (arterial catheter - venipuncture) was -0.3%(upper limit of one-sided 95%CI,+0.3%). The upper limit of the 95%CI did not exceed the predefined margin of+2.0%, establishing noninferiority (P for noninferiority< .001). Obtaining blood cultures from arterial catheters is an acceptable alternative to venipuncture in critically ill patients. University Hospital Medical Information Network Center (UMIN-CTR); No.: UMIN000035392; URL: https://center6.umin.ac.jp/.

Клініко-сонографічні показники як діагностичні критерії інфекційного мононуклеозу в дітей

Актуальність. Значний поліморфізм клінічних проявів інфекційного мононуклеозу, поліорганність ураження, часта відсутність чітких клініко-параклічних критеріїв та відстроченість результатів доступних лабораторних тестів, а іноді і неможливість їх проведення утруднюють діагностику захворювання на догоспітальному етапі та при надходженні до стаціонару. Мета дослідження: оптимізувати діагностику та лікування інфекційного мононуклеозу в дітей шляхом вивчення сучасних особливостей перебігу та аналізу діагностичної цінності клінічних та інструментальних показників у верифікації захворювання. Матеріали та методи. На базі інфекційного боксованого відділення крапельних інфекцій КМУ «Обласна дитяча клінічна лікарня» (м. Чернівці) обстежені 65 дітей, хворих на інфекційний мононуклеоз, які знаходилися на стаціонарному лікуванні в період 2014–2015 рр., першу клінічну групу (І) сформували 42 дитини, заключний клінічний діагноз захворювання у яких верифіковано на підставі комплексу клініко-гематологічних критеріїв, до другої (ІІ) клінічної групи порівняння увійшли 23 дитини, хворі на серологічно підтверджений інфекційний мононуклеоз. За основними клінічними ознаками групи спостереження вірогідно не відрізнялися. Результати. Установлено, що для хворих на інфекційний мононуклеоз дітей характерні клінічні особливості, зокрема раптовий початок захворювання (у 93,8 %) із лихоманки, вищої за 37,5 °С (у 80 %), наявність ексудативного тонзиліту (у 81,6 %), підщелепної та шийної лімфаденопатії (у 90,7 %), утрудненого носового дихання (у 78,4 %) та гугнявості голосу (у 73,8 %). У підтвердженні інфекційного мононуклеозу Епштейна — Барр-вірусної етіології явища ексудативного тонзиліту та лімфаденопатії виявилися високочутливими (90 та 95 % відповідно), проте із значною часткою хибнопозитивних результатів. Висновок. Таким чином, з урахуванням недостатньої діагностичної цінності клініко-анамнестичних та сонографічних показників у виявленні інфекційного мононуклеозу Епштейна — Барр-вірусної етіології в дітей, що підтверджувалося низькими значеннями відношення правдоподібності та показників ризику, використання їх доцільне лише в комплексі.

Place of serological test-systems for detection of antibodies to SARS-CoV2 in emergency cardiac surgery

The article reveals the need for a comprehensive laboratory assessment of testing for antibodies to SARS-CoV-2. In progress it is focused on the possible product of laboratory testing studies of false-positive results caused by the presence of human serum antibodies in that cross reacting with SARS-CoV-2 proteins. It is concluded that in order to reduce the proportion of false positive results of the study require the use of confirmatory test.

Evaluation of Three Commercial Interferon-γ Assays in a Bovine Tuberculosis Free Population.

The interferon-γ assay has been used worldwide as an ancillary test for the diagnosis of bovine tuberculosis (bTB). This study aimed to describe, based on the bTB-free status in Switzerland, the difference of applying a more stringent cutoff point of 0.05 compared with 0.1 for bTB surveillance. Moreover, the effect of time between blood collection and stimulation, culture results, optical density values, and the influence of testing different breeds were evaluated. Blood samples from a total of 118 healthy cows older than 6 months were tested with three commercial interferon-gamma assays. To confirm the bTB-free status of the tested animals and to investigate potential cross-reactions with nontuberculous mycobacteria, pulmonary and abdominal lymph nodes in addition to ileal mucosa from each cattle were used for the detection of viable Mycobacteria spp. by specific culture. Significant differences regarding the proportion of false-positive results between the two Bovigam tests and between Bovigam 2G and ID Screen were found. Samples analyzed with Bovigam 2G were 2.5 [95% confidence interval (CI) 1.6–3.9] times more likely to yield a false-positive test result than samples analyzed with Bovigam TB. Similarly, the odds ratio (OR) for testing samples false-positive with ID Screen compared with Bovigam TB was 1.9 (95% CI 1.21–2.9). The OR for testing false-positive with ID Screen compared with Bovigam 2G was less to equally likely with an OR of 0.75 (95% CI 0.5–1.1). When using a cutoff of 0.05 instead of 0.1, the OR for a false-positive test result was 2.2 (95% CI 1.6–3.1). Samples tested after 6 h compared with a delayed stimulation time of 22–24 h were more likely to yield a false-positive test result with an OR of 3.9 (95% CI 2.7–5.6). In conclusion, applying a more stringent cutoff of 0.05 with the Bovigam 2G kit generates a questionable high number of false-positive results of one of three tested animals. Furthermore, specific breeds might show an increased risk to result false-positive in the Bovigam 2G and the ID Screen assays.

Screening for retinoblastoma: an evidence review of the validity and use of the red reflex test

Abstract Background Retinoblastoma is the most common intraocular malignancy of childhood, the most common presenting signs of which are leucocoria and strabismus. In Ireland, there are on average less than 5-7 cases annually. Early detection of this sight and life-threatening malignancy is important to enable urgent specialist ophthalmology referral for assessment. An evidence review was sought by the Health Service Executive Steering Group for the Revised Child Health Programme to examine the validity and use of the red reflex test in Ireland and internationally as a screening test for retinoblastoma. Methods An electronic literature search was conducted to identify relevant peer-reviewed publications using the database Pubmed. A hand search of reference lists of suitable articles was conducted to check for additional material. Publications pertaining to national and international retinoblastoma screening practices were sourced via internet searches using Google. The relevant grey literature was explored. Results There is very limited data on the validity of the red reflex test as a screening test for retinoblastoma. Despite potentially raising a high proportion of false positive results, it is a low-cost, non-invasive, quick and acceptable test. In Ireland and the UK, retinoblastoma is universally screened for using the red reflex test within 72 hours of birth and at 6-8 weeks of age. Detection of a white, absent or asymmetrical red reflex prompts urgent referral to a specialist ophthalmology service. Many cases of retinoblastoma in developed countries are brought to clinical attention after an eye abnormality is noticed by a parent. Conclusions The red reflex test is a valuable screening tool which is used internationally as part of newborn screening for eye pathology including retinoblastoma. The evidence synthesised in this review will inform educational initiatives in Ireland to improve awareness and detection of this malignancy among healthcare providers and parents. Key messages Early detection of retinoblastoma is important to enable urgent specialist ophthalmology referral for assessment. The red reflex test is a valuable screening tool which is used internationally as part of newborn screening for eye pathology including retinoblastoma.

The diagnosis of metastatic uveal melanoma. What has changed during 10 years?

Uveal melanoma is the most common intraocular malignancy. Despite significant progress in the treatment of the primary tumor, uveal melanoma continues to be the most aggressive tumor due to its high potential for hematogenous metastatic spread. Uveal melanoma metastases are located mostly in the liver. Overall survival of patients with liver metastases is 4 to 15 months. There is no adjuvant systemic therapy to prevent metastases of uveal melanoma. In this paper, we aim to analyze achievement in diagnosis of metastatic uveal melanoma made during the last 10 years and to show advantages and disadvantages of the main diagnostic methods. The last years showed the emergence of understanding the differences between skin and uveal melanoma based on different molecular genetic abnormalities and different signaling pathways of these tumors. The success of target treatments for skin melanoma is not applicable to uveal melanoma. Skin and uveal melanoma responds differently to immune checkpoint inhibitors. Insufficient efficacy of systemic chemotherapy, immune and target therapy has made it necessary to develop techniques of local chemoembolization and radioembolization of uveal melanoma metastases. At present, there are no available assessment algorithms for the management of patients with uveal melanoma and suspected metastases. Ultrasonography, if seen as available techniques for radiology diagnostics, should be enhanced either by the intravenous contrast, or by qualifying computed tomography. The use of positron emission tomography / computed tomography has not demonstrated the maximal diagnostic value in identification of liver metastases, and, taken into account its high costs, low availability, and large radiation dose, it cannot be considered as a feasible method for every 6 months' application. The most effective diagnostic method is magnetic resonance imaging with the liver-specific contrast agents, due to the possibility to detect metastases of less than 1 cm in diameter. However, this technique has not been widely accepted clinically due to high costs, contraindications and a big proportion of false positive results. Current armamentarium of radiation techniques that could be potentially applicable for visualization of hepatic focal abnormalities is rather impressive and is being continuously updated; however, the problem of the metastatic uveal melanoma diagnosis remains unsolved.

Complex radiologic imaging of early breast cancer (literature review)

Clinicoroentgenological diagnosis of early breast cancer - BC (non-invasive or invasive small-sized cancers) is difficult due to the absence of any characteristic clinical symptoms and pathognomonic roentgenological signs of the malignant process. Screening of BC has shown to be one of the most successful projects for early diagnosis of malignancies, but the probability to receive false negative results using screening mammography reaches 12%, and, on the one hand, this is due to interval cancers, and on the other hand - to defects in the primary screening. Among the factors associated with the likelihood of ineffective screening of BC, the most authors highlight such as high breast density, preceding the breast biopsy for a benign process, young age, as well as the use of hormone replacement therapy. The main methods of instrumental BC diagnostics are mammography, ultrasound (US), magnetic resonance imaging (MRI) and positron emission tomography (PET). Mammography is the "gold standard" for both screening and best diagnostics, but is characterized by a high proportion of both false positive and false negative results, and this can be partially solved by the use of digital mammography with tomosynthesis (performing a series of mammography images obtained at different angles and producing the focused 3-D images). Contrast enhanced mammography allows to identify angiogenesis in the area of the predicted malignancy, but is characterized by a high radiation exposure. Breast ultrasound is characterized by low specificity of the method and the high dependence of the result of data interpretation depending on physician qualifications. MRI of the breast for screening is characterized by high sensitivity, but also high cost and high proportion of false positive results. The role of PET/computer tomography in the diagnosis of early BC remains unclear, and the informative value of research in patients with nonpalpable tumors is extremely low. The roentgenological picture of early BC is widely variable; characteristic features include the presence of clustered calcifications, lumps with jagged edges, rough multinodular lumps. However, in a significant proportion of women the only manifestation of early BC is the presence of microcalcinates. Careful analysis of the localization and the shape of microcalcinates and basic characteristics allows correctly interpret the roentgenological diagnosis and helps to choose the optimal diagnostic and treatment algorithm.

Analysis of DNA Methylation at Specific Loci in Stool Samples Detects Colorectal Cancer and High-Grade Dysplasia in Patients With Inflammatory Bowel Disease

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are at increased risk for colorectal cancer (CRC). Analyses of DNA methylation patterns in stool samples have been reported to detect CRC in patients with IBD. We sought to validate these findings in larger cohorts and assess the accuracy of analysis of DNA methylation patterns in stool for detection of CRC and high-grade dysplasia (HGD) normalized to methylation level atZDHHC1. We obtained buffered, frozen stool samples from a US case-control study and from 2 European surveillance cohorts (referral or population based) of patients with chronic ulcerative colitis (n= 248), Crohn's disease (n= 82), indeterminate colitis (n= 2), or IBD with primary sclerosing cholangitis (n= 38). Stool samples were collected before bowel preparation for colonoscopy or at least 1 week after colonoscopy. Among the study samples, stools from individuals with IBD but without neoplasia were used as controls (n= 291). DNA was isolated from stool, exposed to bisulfite, and then assayed by multiplex quantitative allele-specific real-time target and signal amplification. We analyzed methylation levels of BMP3, NDRG4, VAV3, and SFMBT2 relative to the methylation level of ZDHHC1, and compared these between patients with CRC or HGD and controls. Levels of methylation at BMP3 and VAV3, relative to ZDHHC1 methylation, identified patients with CRC and HGD with an area under the curve value of 0.91 (95% CI, 0.77-1.00). Methylation levels at specific promotor regions of these genes identified 11 of the 12 patients with CRC and HGD, with 92% sensitivity (95% CI, 60%-100%) and 90% specificity (95% CI, 86%-93%). The proportion of false-positive results did not differ significantly among the case-control, referral cohort, and population cohort studies (P= .60) when the 90% specificity cut-off from the whole sample set was applied. In an analysis of stool samples from 3 independent studies of 332 patients with IBD, we associated levels of methylation at 2 genes (BMP3 and VAV3), relative to level of methylation at ZDHHC1, with detection of CRC and HGD. These methylation patterns identified patients with CRC and HGD with more than 90% specificity, and might be used in CRC surveillance.

Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics

BackgroundThe use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require interpretation. Therefore, prediction of the effects of missense mutations using in silico tools has become a frequently used approach. Aim of this study was to assess the reliability of in silico prediction as a basis for clinical decision making in the context of hereditary breast and/or ovarian cancer.MethodsWe tested the performance of four prediction tools (Align-GVGD, SIFT, PolyPhen-2, MutationTaster2) using a set of 236 BRCA1/2 missense variants that had previously been classified by expert committees. However, a major pitfall in the creation of a reliable evaluation set for our purpose is the generally accepted classification of BRCA1/2 missense variants using the multifactorial likelihood model, which is partially based on Align-GVGD results. To overcome this drawback we identified 161 variants whose classification is independent of any previous in silico prediction. In addition to the performance as stand-alone tools we examined the sensitivity, specificity, accuracy and Matthews correlation coefficient (MCC) of combined approaches.ResultsPolyPhen-2 achieved the lowest sensitivity (0.67), specificity (0.67), accuracy (0.67) and MCC (0.39). Align-GVGD achieved the highest values of specificity (0.92), accuracy (0.92) and MCC (0.73), but was outperformed regarding its sensitivity (0.90) by SIFT (1.00) and MutationTaster2 (1.00). All tools suffered from poor specificities, resulting in an unacceptable proportion of false positive results in a clinical setting. This shortcoming could not be bypassed by combination of these tools. In the best case scenario, 138 families would be affected by the misclassification of neutral variants within the cohort of patients of the German Consortium for Hereditary Breast and Ovarian Cancer.ConclusionWe show that due to low specificities state-of-the-art in silico prediction tools are not suitable to predict pathogenicity of variants of uncertain significance in BRCA1/2. Thus, clinical consequences should never be based solely on in silico forecasts. However, our data suggests that SIFT and MutationTaster2 could be suitable to predict benignity, as both tools did not result in false negative predictions in our analysis.

A computationally simple central monitoring procedure, effectively applied to empirical trial data with known fraud

ObjectivesCentral monitoring of multicenter clinical trials becomes an ever more feasible quality assurance tool, in particular for the detection of data fabrication. More widespread application, across both industry sponsored as well as academic clinical trials, requires central monitoring methodologies that are both effective and relatively simple in implementation. Study Design and SettingWe describe a computationally simple fraud detection procedure intended to be applied repeatedly and (semi-)automatically to accumulating baseline data and to detect data fabrication in multicenter trials as early as possible. The procedure is based on anticipated characteristics of fabricated data. It consists of seven analyses, each of which flags approximately 10% of the centers. Centers that are flagged three or more times are considered “potentially fraudulent” and require additional investigation. The procedure is illustrated using empirical trial data with known fraud. ResultsIn the illustration data, the fraudulent center is detected in most repeated applications to the accumulating trial data, while keeping the proportion of false-positive results at sufficiently low levels. ConclusionThe proposed procedure is computationally simple and appears to be effective in detecting center-level data fabrication. However, assessment of the procedure on independent trial data sets with known data fabrication is required.

Proportion of false-positive lesions at interim and end-of-treatment FDG-PET in lymphoma as determined by histology: Systematic review and meta-analysis

PurposeTo systematically review and meta-analyze the proportion of false-positive lesions at interim and end-of-treatment 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in lymphoma using biopsy as reference standard. Materials and methodsMedline was searched for original studies. Methodological quality of included studies was evaluated, and results were meta-analytically summarized using random effects (in case of interstudy heterogeneity [I2≤50%]) or fixed effects (in case of no interstudy heterogeneity [I2>50%]). ResultsEleven studies, comprising 139 patients who underwent biopsy of an FDG-avid lesion during or after completion of antilymphoma treatment, were included. Overall methodological quality was moderate. The proportion of false-positive results among all biopsied FDG-avid lesions at PET performed during of after completion of treatment ranged between 7.7% and 90.5% (the vast majority was due to inflammatory changes), with a weighted summary proportion (random effects, I2=75.7%) of 55.7% (95% confidence interval [CI]: 32.6–76.6%). There were no available studies on interim FDG-PET in Hodgkin lymphoma. The pooled summary false-positive proportions were 83.0% (95% CI: 72.0%–90.2%) for interim FDG-PET in non-Hodgkin lymphoma (fixed effects, I2=27.7%), 23.1% (95% CI: 4.7%–64.5%) for end-of-treatment FDG-PET in Hodgkin lymphoma (random effects; I2=67.1%), and 31.5% (95% CI: 3.9%–83.9%) for end-of-treatment FDG-PET in non-Hodgkin lymphoma (random effects, I2=68.3%). ConclusionBoth interim and end-of-treatment FDG-PET scans in patients with lymphoma suffer from a very high number of false-positive FDG-avid lesions. This finding, in combination with the previously reported high number of false-negative FGD-PET scans for residual disease detection, suggests that the role of interim and end-of-treatment FDG-PET should be reconsidered.

Comprehensive retrospective evaluation of existing in vitro chromosomal aberration test data by cytotoxicity index transformation

New OECD test guidelines have been issued, in which the cytotoxicity index relative cell count (RCC) is replaced with a new index, RICC or RPD (relative increase in cell count/relative population doubling), with the goal of reducing the high proportion of false positive results in in vitro chromosomal aberration tests. Using a mathematical approach to estimate new indices from the RCC, we constructed an evaluation flow that quantitatively estimates how often the previous test conclusions change when applying the updated cytotoxicity criteria. The new evaluation flow was applied to a retrospective evaluation of 285 chemicals in two databases. The effects of the employment of new cytotoxicity indices are investigated at a large scale. Using the new evaluation flow, 90 chemicals were estimated as positive, 39 were designated as estimated negative (13 probably negative and 26 possibly negative), and 140 were designated as negative. Moreover, we also applied a prioritization index to indicate the likelihood of a chemical being re-evaluated as negative and assigned priorities for testing. Most of the chemicals that were designated as estimated negative and had negative results in the in vivo micronucleus tests were considered as false-positives that would be correctly judged under the new test guideline. Furthermore, statistical analysis of the frequency of estimated negatives revealed that the results for Ames-positive chemicals, especially those with a strong response, are unlikely to change. Therefore, we concluded that the new indices would likely reduce the proportion of false positive results and not increase the proportion of false negative results. This study is the first report of a comprehensive re-evaluation of test results in terms of new cytotoxicity indices. The evaluation flow we have developed facilitates efficient retrospective evaluation of genotoxicity.

Impact of the radiographic examination on diagnosis and treatment decision of caries lesions in primary teeth--the Caries Detection in Children (CARDEC-01) trial: study protocol for a randomized controlled trial.

BackgroundAlthough most clinical guidelines throughout the world indicate that clinicians take two bitewings for detecting caries lesions in primary molars of all children, evidence for this recommendation is essentially based on cross-sectional studies performed in laboratory settings or using convenience samples. The benefits and impact of performing radiographs on diagnosis and treatment decision of caries lesions in primary teeth, mainly considering relevant outcomes for patients, have not been evaluated yet. Thus, the aim of this randomized clinical trial will be to evaluate the impact of performing radiographic examination adjunct to the visual inspection for detecting and making treatment decision regarding caries lesions in primary teeth compared with visual inspection performed alone. We will consider different outcomes related to children's health and welfare.Methods/DesignTo reach this objective, 250 children ages 3 to 6 years who sought dental treatment in our dental school will be randomly allocated in two groups according to the diagnostic strategy used for caries detection: visual inspection performed alone or visual inspection associated to radiographic examination. Two trained and calibrated examiners will carry out the examinations and elaborate the treatment decision plan. Then, children will be treated and followed up for 2 years, with evaluations after 12 and 24 months after the inclusion of children in the study. Children will also return after 6 and 18 months to reinforce the preventive orientations. Primary outcome will be the number of dental surfaces in need of dental treatment at the follow-up. Secondary outcomes will be the components of the primary outcome separately, as well as, proportion of false-positive results, the oral health-related quality of life, cost-efficacy, cost-adjusted life years, and number of new lesions in the first permanent molars.DiscussionOur working hypothesis is that radiographic examination would actually exert little influence on patient-centered outcomes, and visual inspection would be enough as diagnostic strategy for caries detection in primary teeth.Trial registrationNCT02078453. Registered 4 March 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1196-5) contains supplementary material, which is available to authorized users.

Clinical significance of incidental findings on staging positron emission tomography for oesophagogastric malignancies.

The aim of this retrospective study was to determine the clinical significance of incidental findings detected on positron emission tomography (PET) in patients undergoing staging of oesophagogastric malignancies. Patients with oesophagogastric malignancies who underwent PET between June 2007 and May 2012 were included in the study. PET was performed according to hospital protocol. All imaging was interpreted by two consultant radiologists in nuclear medicine. Incidental findings that were unrelated to the primary malignancy were recorded and patients were recommended to have further investigations (imaging, endoscopy and biopsy). Overall, 333 patients (240 male, 93 female; mean age: 67 years) with upper gastrointestinal malignancies were eligible for inclusion in the study. Eighty-nine of these patients had PET demonstrating one or more incidental findings. Two patients were found to have a second primary malignancy. One patient had a distant metastasis of his primary cancer and six patients had a premalignant lesion. In this study, incidental findings were discovered in 26.7% of patients with known oesophagogastric cancer. A second primary cancer or premalignant lesion was found in 8.4% of patients with incidental findings. Patients with these findings should be investigated to rule out further malignancy. There were a high proportion of false positive results in our study. It is recommended that each patient is considered on an individual basis and assessed with simultaneous PET and computed tomography.

Performances of SD Bioline Malaria Ag-P.F/Pan RDT for the Diagnosis of Malaria in Febrile Patients Living In Gabon, Central Africa

The SD Bioline malaria Ag- Pf/Pan performances were evaluated for malaria species detection in 215 febrile patients living in Gabon, using microscopy as gold standard. Malaria parasites were identified in 94 (43.7%) individuals by microscopy, and 104 (48.4%) patients tested positive by the RDT. The SD Bioline Ag-Pf/Pan global sensitivity was 96.8%. All the non-falciparum malaria species infections were correctly diagnosed by the rapid test. The specificity was of 89.3% and the false positive (FP) rate of 12.5%. The test sensitivity significantly increased with parasitaemia, being of 88.9% for parasite density below 100/ µL and 98.5% at density higher than 500 parasites/ µL (p<0.01). Among the patients with a negative blood smear, the proportion of FP results was 21.0% in those previously-treated with an antimalarial drug before the consultation, and 8.8% in individuals without self-medication. SD Bioline Ag-Pf/ Pan RDT represents a good alternative to microscopy for the diagnosis of Plasmodium spp infection.

Likelihood of early detection of breast cancer in relation to false-positive risk in life-time mammographic screening: population-based cohort study

BackgroundWomen require balanced, high-quality information when making an informed decision on screening benefits and harms before attending biennial mammographic screening. Patients and methodsThe cumulative risk of a false-positive recall and/or (small) screen-detected or interval cancer over 13 consecutive screening examinations for women aged 50 from the start of screening were estimated using data from the Nijmegen programme, the Netherlands. ResultsWomen who underwent 13 successive screens in the period 1975–1976 had a 5.3% cumulative chance of a screen-detected cancer, with a 4.2% risk of at least one false-positive recall. The risk of being diagnosed with interval cancer was 3.7%. Two decades later, these estimates were 6.9%, 7.3% and 2.9%, respectively. The chance of detection of a small, favourable invasive breast cancer, anticipating a normal life-expectancy, rose from 2.3% to 3.7%. Extrapolation to digital screening mammography indicates that the proportion of false-positive results will rise to 16%. ConclusionDutch women about to participate in the screening programme can be reassured that the chance of false-positive recall in the Netherlands is relatively low. A new screening policy and improved mammography have increased the detection of an early screening carcinoma and lowering the risk of interval carcinoma.