Number Of False Negatives Research Articles

Effect of incomplete registration at general practices on the annual prevalence of treated asthma

ABSTRACTBackgroundAnnual prevalence of 'treated asthma' can be estimated using primary care routine data. However, the denominator may include people with incomplete registration at general practices (GP) in the year of estimation. Patients with incomplete registrations who actually take medications but have no recorded prescriptions represent false-negative cases leading to underestimated prevalence.
 ObjectivesTo estimate the effect of incomplete GP registrations on the annual prevalence of treated asthma in Wales.
 MethodsUsing the GP dataset of the Secure Anonymised Information Linkage (SAIL) Databank, we created a denominator of people who lived in Wales and registered at Welsh GPs for any period during 2010. For the uncorrected prevalence, the numerator included people who ever had a recorded asthma diagnosis and any current recorded asthma prescriptions. For the corrected prevalence, we estimated the number of false-negatives and added them to the numerator. To do that, we calculated, for asthma patients with incomplete registrations and no recorded prescriptions, the sum of probabilities of having prescriptions if they had complete registrations. We estimated the absolute and relative increases in the prevalence at national and local authority levels as well as for the subpopulation with incomplete registration.
 ResultsThe denominator included 2,221,967 people, of whom 94.8% had complete GP registration in 2010. Without correction, the numerator included 132,439 patients giving a prevalence of 5.96% [95% CI 5.93-5.99]. By adding estimated 1,801 false-negative cases to the numerator, the adjusted prevalence is 6.04% [95% CI 6.01-6.07] with absolute and relative increases of 0.08% and 1.36%, respectively. At the local authority level, the relative increase ranged from 0.47% for Blaenau Gwent to 3.94% for Monmouthshire. Among the subpopulation with incomplete registration (5.1%), the prevalence increased by 68.0% from 2.32% to 3.91%.
 ConclusionIn Wales, which has a highly stable population, incomplete GP registration has negligible effect on the prevalence of treated asthma at a national level, although it was more significant for sub-regions with less stable populations. This correction method could be useful for more accurate estimation of asthma burden and the prevalence of active disease in highly dynamic populations.
 FundingHealth and Care Research Wales and ABMU Health Board. Supported by Asthma UK Centre for Applied Research [AUK-AC-2012-01].

Transductive learning as an alternative to translation initiation site identification

BackgroundThe correct protein coding region identification is an important and latent problem in the molecular biology field. This problem becomes a challenge due to the lack of deep knowledge about the biological systems and unfamiliarity of conservative characteristics in the messenger RNA (mRNA). Therefore, it is fundamental to research for computational methods aiming to help the patterns discovery for identification of the Translation Initiation Sites (TIS). In the field of Bioinformatics, machine learning methods have been widely applied based on the inductive inference, as Inductive Support Vector Machine (ISVM). On the other hand, not so much attention has been given to transductive inference-based machine learning methods such as Transductive Support Vector Machine (TSVM). The transductive inference performs well for problems in which the amount of unlabeled sequences is considerably greater than the labeled ones. Similarly, the problem of predicting the TIS may take advantage of transductive methods due to the fact that the amount of new sequences grows rapidly with the progress of Genome Project that allows the study of new organisms. Consequently, this work aims to investigate the transductive learning towards TIS identification and compare the results with those obtained in inductive method.ResultsThe transductive inference presents better results both in F-measure and in sensitivity in comparison with the inductive method for predicting the TIS. Additionally, it presents the least failure rate for identifying the TIS, presenting a smaller number of False Negatives (FN) than the ISVM. The ISVM and TSVM methods were validated with the molecules from the most representative organisms contained in the RefSeq database: Rattus norvegicus, Mus musculus, Homo sapiens, Drosophila melanogaster and Arabidopsis thaliana. The transductive method presented F-measure and sensitivity higher than 90% and also higher than the results obtained with ISVM. The ISVM and TSVM approaches were implemented in the TransduTIS tool, TransduTIS-I and TransduTIS-T respectively, available in a web interface. These approaches were compared with the TISHunter, TIS Miner, NetStart tools, presenting satisfactory results.ConclusionsIn relation to precision, the results are similar for the ISVM and TSVM classifiers. However, the results show that the application of TSVM approach ensured an improvement, specially for F-measure and sensitivity. Moreover, it was possible to identify a potential for the application of TSVM, which is for organisms in the initial study phase with few identified sequences in the databases.

Risk factors for failure to detect bovine tuberculosis in cattle from infected herds across Northern Ireland (2004–2010)

Correctly identifying animals that are truly infected with a pathogen using ante-mortem tests is the cornerstone of any disease eradication programme. Failure to identify all infected animals will impede the progress towards controlling and eradicating disease and may also have unforeseen consequences when specific prevention measures are in place to avoid animal-to-animal transmission. In the case of bovine tuberculosis (bTB), the screening ante-mortem test, the Single Comparative Intradermal Tuberculin Test (SCITT), can exhibit moderate sensitivity which can result in a “hidden burden” of infection residing within the population. Using an animal-level dataset relating to the disclosure of infected cattle with Mycobacterium bovis, the causative agent of bTB within infected herds in Northern Ireland, we investigated what factors influenced the probability of an animal being a false-negative when truly infected (using post-mortem (PM) microbiological culture confirmation results to assess infection status).We found that different risk factors affected the probability of a test-negative outcome on infected animals depending on the ante-mortem test or their combination (SICTT and/or interferon gamma (IFN-ɣ) testing). Using multivariable models, SCITT disclosure performance varied significantly by age, location (region), and production type. The IFN-ɣ tests were significantly affected by region or season, but these effects depended on the cut-off used during interpretation of the test which affected the tests characteristics. Parallel use of SCITT and IFN-ɣ tests resulted in the least number of false-negatives, and their disclosure was affected by season and age-class.Understanding the factors that lead to the non-disclosure of infected animals is essential to optimise large-scale bTB disease eradication programmes.

TxRace

Detecting data races is important for debugging shared-memory multithreaded programs, but the high runtime overhead prevents the wide use of dynamic data race detectors. This paper presents TxRace, a new software data race detector that leverages commodity hardware transactional memory (HTM) to speed up data race detection. TxRace instruments a multithreaded program to transform synchronization-free regions into transactions, and exploits the conflict detection mechanism of HTM for lightweight data race detection at runtime. However, the limitations of the current best-effort commodity HTMs expose several challenges in using them for data race detection: (1) lack of ability to pinpoint racy instructions, (2) false positives caused by cache line granularity of conflict detection, and (3) transactional aborts for non-conflict reasons (e.g., capacity or unknown). To overcome these challenges, TxRace performs lightweight HTM-based data race detection at first, and occasionally switches to slow yet precise data race detection only for the small fraction of execution intervals in which potential races are reported by HTM. According to the experimental results, TxRace reduces the average runtime overhead of dynamic data race detection from 11.68x to 4.65x with only a small number of false negatives.

Appendicitis Ultrasound: Comparison Study of the Radiology Resident to the Technologist and Attending

Background and objects: Community hospitals and academic centers may not always have a radiologist or sonographer on site, and the responsibility of US performance after hours maybe left to a resident. The purpose of this study was to evaluate a growing concern at our institution that a higher numbers of pediatric CT scans were being conducted overnight for the evaluation of acute appendicitis, as a result of a perception that scans performed by residents were not as accurate as those performed by technologists and/or attending. Materials and methods: 573 patients initially evaluated by ultrasound for appendicitis, from April 2008 to March 2014. Studies were distinguished by either resident or technologist and attending (TA) performing the procedure. The junior resident was in the first to third years of training with at least 8 weeks of US experience. Follow-up computed tomography and operative reports were reviewed to determine if appendicitis was later confirmed. Results: Of 462 studies in the pediatric non-pregnant group, ages one to eighteen years, 261 (56.5%) were performed by a junior resident and 201 (43.5%) were performed by the TA group. The sensitivity of diagnosing acute appendicitis in the first ultrasound by the resident and TA groups were 59% and 67%, respectively (p=0.73). Additional testing ordered after a negative initial US was higher in the resident group than the TA group, 85 (39.5%) and 46 (26.4%), respectively (p=0.010). The number of false negatives in the overall, resident and TA groups were 35 (38%), 24 (41%) and 11 (33%), respectively (p=0.68). Conclusion: Although appendicitis US has been traditionally touted as operator dependent, there was no statistical difference in this study between residents and attendings of varying levels of experience. Additionally, more follow up studies were ordered when the initial study was negative and performed by the resident.

Power, FDR and conservativeness of BB-SGoF method

Beta-binomial sequential goodness-of-fit (or BB-SGoF) method for multiple testing has been recently proposed as a suitable modification of the sequential goodness-of-fit (SGoF) multiple testing method when the tests are correlated in blocks. In this paper we investigate for the first time the power, the FDR and the conservativeness of BB-SGoF in an intensive Monte Carlo simulation study. Important features such as automatic selection of the number of existing blocks and preliminary testing for independence are explored. Our study reveals that (a) BB-SGoF method roughly maintains the properties of original SGoF in the dependent case, reporting a small value for the probability that the number of false positives exceeds the number of false negatives with p value below $$\gamma $$?; (b) BB-SGoF weakly controls for FDR even when the beta-binomial model is violated and the number of blocks $$k$$k is unknown; and that (c) the loss of power of the automatic selector for the number of blocks relative to the benchmark method which uses the true $$k$$k varies depending on the proportion and the type (strong, intermediate or weak) of the effects, being strongly influenced by the within-block correlation too.

Prediction of genotoxic potential of cosmetic ingredients by an in silico battery system consisting of a combination of an expert rule-based system and a statistics-based system.

Genotoxicity is the most commonly used endpoint to predict the carcinogenicity of chemicals. The International Conference on Harmonization (ICH) M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk offers guidance on (quantitative) structure-activity relationship ((Q)SAR) methodologies that predict the outcome of bacterial mutagenicity assay for actual and potential impurities. We examined the effectiveness of the (Q)SAR approach with the combination of DEREK NEXUS as an expert rule-based system and ADMEWorks as a statistics-based system for the prediction of not only mutagenic potential in the Ames test, but also genotoxic potential in mutagenicity and clastogenicity tests, using a data set of 342 chemicals extracted from the literature. The prediction of mutagenic potential or genotoxic potential by DEREK NEXUS or ADMEWorks showed high values of sensitivity and concordance, while prediction by the combination of DEREK NEXUS and ADMEWorks (battery system) showed the highest values of sensitivity and concordance among the three methods, but the lowest value of specificity. The number of false negatives was reduced with the battery system. We also separately predicted the mutagenic potential and genotoxic potential of 41 cosmetic ingredients listed in the International Nomenclature of Cosmetic Ingredients (INCI) among the 342 chemicals. Although specificity was low with the battery system, sensitivity and concordance were high. These results suggest that the battery system consisting of DEREK NEXUS and ADMEWorks is useful for prediction of genotoxic potential of chemicals, including cosmetic ingredients.

Egg sampling as a possible alternative to blood sampling when monitoring the exposure of yellow-legged gulls (Larus michahellis) to avian influenza viruses

We explored whether antibody detection in egg yolks could serve as an alternative to antibody detection in plasma samples when monitoring yellow-legged gulls (Larus michahellis) for exposure to avian influenza viruses (AIVs). We tested female plasma and eggs for anti-AIV antibodies and used the data we obtained to check whether the two sample types yielded the same antibody status (positive or negative) and to compare the antibody prevalence estimated from the blood data with that estimated from the yolk data. Our results showed that sampling one egg per clutch, regardless of that egg's position in the laying sequence, is sufficient to provide an unbiased estimate of antibody prevalence across clutches. The results also showed that almost 25% of the clutches laid by positive females contained only antibody-negative eggs, which suggests that yolk samples might underestimate female antibody prevalence. However, this result may stem from differences in the methods used to assess plasma versus yolk antibody status. Further research is needed to clarify this issue; while the number of false negatives could be reduced by adapting antibody detection techniques, it may be that they are an unavoidable consequence of natural avian maternal transfer dynamics.

Effects of variation of sentinel lymph nodes submitted during breast cancer sugery: Analysis of practice variation and costs.

94 Background: Routine node evaluation involves simple bivalving the node with slides made from the resultant surfaces. SLNs are more thoroughly evaluated with 2-3 mm slices and histologic evaluation of each slice, resulting in many more slides to review. These slides would often have immunohistochemical analysis adding to the time and cost. In early studies of SLN efficacy and accuracy, the mean number of nodes was between 2 and 3 per patient though with some variation. As the number of submitted SLNs increases, the concern of benefit of the procedure comes into question. This is a retrospective examination of all SLN procedures for the year 2012 to examine the variation in the number of SLNs submitted for focused pathologic evaluation. Variation in the number of nodes submitted by surgeon is determined along with the associated costs of the pathologic evaluation. In addition, intraoperative evaluation of lymph node status may be useful to allow for immediate axillary node dissection during the initial operation. Utilization of this procedure was also examined to determine ultimate correlation with permanent pathologic evaluation. Methods: Retrospective examination of all breast cancer patients >=18 yrs who underwent SLN procedures during 2012. Introperative evaluation of lymph node for metastatic disease was also examined for correlation with permanent pathologic result. Results: 259 cases among 21 surgeons had touch prep performed. True positive number: 29. True negative number: 224. False negative number: 6. Fasle negative rate (FNR): 17.14%. Cost Effectiveness Evaluation: CPT 88307 - surg path gross and micro level V. CPT 88342 - Immunohistochemistry. CPT 88333 - Touch Prep. Pathologist time: 30 minutes per case. Conclusions: There is significant variation among surgeons as to number of cases and number of nodes submitted. There is a significantly greater number of sentinel lymph nodes examined by the pathologist as compared to the number of nodes submitted by the surgeon. The frequency of outliers is infrequent, but when it occurs there is significant cost in terms of time and dollars. The false negative rate from pathological evaluation is under study for isolated tumor cells.

Education-corrected CERAD identifies MCI and dementia in Parkinson's disease.

This study examined whether controlling for educational background in the CERAD cognitive screening battery would affect the likelihood of patients with Parkinson's disease to fulfill criteria for mild cognitive impairment (PD-MCI) and dementia (PDD). One-hundred seventeen patients with PD were studied. Cognitive impairment was determined as two subtest scores falling below either the standard cutoff scores or education-corrected cutoff scores. The presence of dementia was determined by clinical interview or Clinical Dementia Rating. Patients were then classified as PD-MCI and PDD according to cognitive test performance and presence/absence of dementia. The number of cognitively impaired patients (PD-MCI or PDD) was significantly higher when education-controlled cutoff scores were used (62.5% vs 38%). Correspondingly, the number of false negatives (demented PD patients performing normally in CERAD) was significantly lower when education-corrected cutoff scores were used (4% vs 10%). Controlling for education increases the sensitivity of the CERAD for PD-MCI and PDD.

To what extent could we detect field defects? An extended empirical study of false negatives in static bug-finding tools

Software defects can cause much loss. Static bug-finding tools are designed to detect and remove software defects and believed to be effective. However, do such tools in fact help prevent actual defects that occur in the field and reported by users? If these tools had been used, would they have detected these field defects, and generated warnings that would direct programmers to fix them? To answer these questions, we perform an empirical study that investigates the effectiveness of five state-of-the-art static bug-finding tools (FindBugs, JLint, PMD, CheckStyle, and JCSC) on hundreds of reported and fixed defects extracted from three open source programs (Lucene, Rhino, and AspectJ). Our study addresses the question: To what extent could field defects be detected by state-of-the-art static bug-finding tools? Different from past studies that are concerned with the numbers of false positives produced by such tools, we address an orthogonal issue on the numbers of false negatives. We find that although many field defects could be detected by static bug-finding tools, a substantial proportion of defects could not be flagged. We also analyze the types of tool warnings that are more effective in finding field defects and characterize the types of missed defects. Furthermore, we analyze the effectiveness of the tools in finding field defects of various severities, difficulties, and types.

Diagnostic accuracy of FDG-PET cancer screening in asymptomatic individuals: use of record linkage from the Osaka Cancer Registry

Whole-body cancer screening with multimodalities including [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) detects a wide range of tumors. This program has been recognized as an option for opportunistic screening, particularly in Japan. However, reports on diagnostic accuracy have been limited. We aimed to evaluate the detectability and related properties of this screening program among asymptomatic individuals in a community setting. The study participants were 1,762 residents of Osaka Prefecture, Japan, who underwent opportunistic cancer screening at Higashitemma Clinic for the first time between November 2004 and December 2005. FDG-PET cancer screening was performed with several imaging modalities (e.g., FDG-PET, computed tomography, magnetic resonance imaging and ultrasonography) and fecal occult blood test. Screening records were linked to the Osaka cancer registry within 1 year after the screening to determine sensitivity, specificity and positive predictive values. After excluding 12 participants with cancer detected before the screening, 33 were identified by the cancer registry to have primary cancers. Of these, the present screening program found that 28 were positive (6 prostate, 5 lung, 5 colorectal, 5 thyroid, 3 liver and 4 others). Sensitivity, specificity and positive predictive values were 84.8 % (28/33, 95 % confidence interval 69.1-93.3), 86.8 % (1,491/1,718, 85.1-88.3) and 10.1 % (28/277, 6.4-12.9), respectively. FDG-PET cancer screening with multimodalities reasonably and accurately detects existing asymptomatic cancer. However, the numbers of false negatives and false positives were not insignificant. Facilities that provide the screening should inform participants of relevant information, including the limitations of this program.

Quality Indicators for Sentinel Node Surgery

Surgical quality has historically been measured on the basis of the short-term morbidity and mortality. However, mortality from and immediate complications associated with breast and axillary surgery are extremely low and, therefore, are not adequate indicators of the quality of a particular operation for a patient with a breast malignancy. Unlike the introduction of novel laparoscopic techniques for abdominal surgery, for which clinical trial evaluation has been infrequent, the sentinel node mapping and nodal dissection (SLND) procedure has undergone intense retrospective and prospective clinical scrutiny throughout its development and widespread inclusion in surgical practice. SLND for breast cancer was introduced over 20 years ago and was performed in association with axillary dissection to identify the sentinel nodes and determine the number of false negatives, thereby ensuring low incidence of inaccurate oncologic staging. The original studies used a single mapping agent; this progressed to use of combination techniques with more than one mapping agent over the next five years. Sentinel lymph node mapping and dissection is now the operation of choice for patients with early-stage breast cancer. Outcomes can now be measured without requiring measurement of the number of false negatives, because use of axillary dissection is now infrequently co-associated with SLND. As novel dyes and agents are being introduced and as indications for SLND among patients with advanced breast cancer after neoadjuvant systemic treatment are expanding, evaluation of alternative indicators will be needed to determine the best indicators of quality for adequate staging and continued low procedural morbidity. Indicators of quality of SLND are reviewed in this paper. How these indicators will aid evaluation of innovative nodal techniques for patients with a breast malignancy is also discussed.

A comparative study of conventional method versus bactec method in bacteriological profile of septicemia

Sepsis is common and also more dangerous in elderly, immune-compromised, and critically ill patients. It occurs in 1–2% of all hospitalizations and accounts for as much as 25% of intensive-care unit (ICU) bed utilization. It is a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis to 40% for severe sepsis to >60% for septic shock. A total of 160 blood samples were collected from patients with suspected septicemia from several wards of Medwin Hospital. Alternate samples were Cultured by Bactec 9050 (Becton Dickinson Microbiology Systems, Sparks, Md) and conventional methods. And 12 random samples were cultured by both Bactec 9050 and conventional methods. It was observed that out of 160 cases 43 (26.9%) of septicemia positive cases were detected by one or the other method. out of 80 samples cultured by Bactec method 29 (36.2%) were Bactec positive cases. And out of 80 samples cultured by Conventional method 14 (17.5%) were Conventional positive cases. In a statistical comparison of Bactec and Conventional method, Sensitivity for Bactec method was seen as 90% whereas for conventional method it was 60%. Bactec method has the highest specificity i.e. 100% whereas Conventional method has 75%. The Bactec performed better than the conventional in overall detection, time to detection, number of false-negatives, and missed episodes of simulated septicemia.

Malaria rapid diagnostic tests: challenges and prospects

In the last decade, there has been an upsurge of interest in developing malaria rapid diagnostic test (RDT) kits for the detection of Plasmodium species. Three antigens - Plasmodium falciparum histidine-rich protein 2 (PfHRP2), plasmodial aldolase and plasmodial lactate dehydrogenase (pLDH) - are currently used for RDTs. Tests targeting HRP2 contribute to more than 90% of the malaria RDTs in current use. However, the specificities, sensitivities, numbers of false positives, numbers of false negatives and temperature tolerances of these tests vary considerably, illustrating the difficulties and challenges facing current RDTs. This paper describes recent developments in malaria RDTs, reviewing RDTs detecting PfHRP2, pLDH and plasmodial aldolase. The difficulties associated with RDTs, such as genetic variability in the Pfhrp2 gene and the persistence of antigens in the bloodstream following the elimination of parasites, are discussed. The prospect of overcoming the problems associated with current RDTs with a new generation of alternative malaria antigen targets is also described.

Introducing Bayesian Thinking to High-Throughput Screening for False-Negative Rate Estimation

High-throughput screening (HTS) has been widely used to identify active compounds (hits) that bind to biological targets. Because of cost concerns, the comprehensive screening of millions of compounds is typically conducted without replication. Real hits that fail to exhibit measurable activity in the primary screen due to random experimental errors will be lost as false-negatives. Conceivably, the projected false-negative rate is a parameter that reflects screening quality. Furthermore, it can be used to guide the selection of optimal numbers of compounds for hit confirmation. Therefore, a method that predicts false-negative rates from the primary screening data is extremely valuable. In this article, we describe the implementation of a pilot screen on a representative fraction (1%) of the screening library in order to obtain information about assay variability as well as a preliminary hit activity distribution profile. Using this training data set, we then developed an algorithm based on Bayesian logic and Monte Carlo simulation to estimate the number of true active compounds and potential missed hits from the full library screen. We have applied this strategy to five screening projects. The results demonstrate that this method produces useful predictions on the numbers of false negatives.

Performance of the Lausanne questionnaire and the 2010 European Society of Cardiology criteria for ECG interpretation in athletes

In recent years various proposals and subsequent changes have been made to improve pre-participation screening (PPS) methods. This study examines the Lausanne questionnaire and the old and new ESC criteria for a positive electrocardiogram (ECG) in athletes. Retrospective cohort study. All consecutive students undergoing a PPS between January and July 2011 were included. The screening consisted of the Lausanne questionnaire, a physical examination, and a 12-lead ECG. A total of 561 students were screened. A total of 310 students (55%) answered positively to one or more of the Lausanne questions and 49 (9%) of these abnormalities were assessed as medically relevant. Physical examination was abnormal in nine (1.6%) students. In total, 120 (21%) ECGs were found positive following the old criteria. According to the new criteria, 68 (12%) ECGs were found positive. Four (already known) congenital cardiac disorders and four new diagnoses were found. When using the new ECG criteria, two out of four new cardiovascular diagnoses would have been missed. The use of the Lausanne questionnaire provides many irrelevant findings causing unnecessary positive screening outcomes. With the new ESC criteria for a positive 12-lead ECG in athletes, the number of false-positive screenings greatly decrease: however, at the cost of an increase in the number of false-negatives. To reach a conclusive judgment on the cost:benefit ratio of PPS, it is necessary to have a validated discriminating questionnaire, specific medical knowledge of PPS and clear definitions of a normal and abnormal 12-lead ECG in athletes.

Potential Use of Contrast-Enhanced Ultrasound (CEUS) in the Detection of Metastatic Superficial Lymph Nodes in Melanoma Patients

Malignant melanoma represents a significant and growing public health burden worldwide. Ultrasonography is the most useful diagnostic modality for regional lymph nodal staging. Because any focal areas of cortical lobulation or thickening-swelling should also be considered as a sign of metastases, we are going to report the usefulness of contrast-enhanced ultrasonography (CEUS) in the differential diagnosis of benign or malignant lymph nodes in patients with malignant melanoma based on blood stream patterns and investigate the diagnostic capability. After the excision of cutaneous melanoma with positive excision margins but with negative sentinel lymph node, 540 patients underwent US of superficial lymph nodes. The inclusion criteria for CEUS consisted of both major signs (absence of the echogenic hilus, round shape, and peripheral capsular vascularity) and minor ones (the presence of focal cortical thickening). The diagnostic capability was evaluated by comparing the cytological findings with the enhancement pattern on CEUS. US in combination with CEUS correctly classified 534/540 patients. CEUS applied to lymph nodes with focal cortical thickening on grayscale US confirmed great sensitivity (0.98) and specificity (0.99) but above all, it showed a markedly improved accuracy of 0.99. The likelihood ratios confirmed the good performance of the methods used. CEUS increases the diagnostic accuracy of US in the differential diagnosis of benign and malignant LNs but it also allows us, when possible, to avoid unnecessary invasive operations such as LN FNAC. Moreover, CEUS may guide FNAC in the case of focal cortical thickening on the basis of hypoperfusion, with a reduction in the number of false negatives and much earlier detection of nodal metastatic foci.

Sample size for detecting transgenic plants using inverse binomial group testing with dilution effect

AbstractIn this study we developed a sample size procedure for estimating the proportion of genetically modified plants (adventitious presence of unwanted transgenic plants, AP) under inverse negative binomial group testing sampling, which guarantees that exactly r positive pools will be present in the sample. To achieve this aim, pools are drawn one by one until the sample contains r positive pools. The use of group testing produces significant savings because groups that contain several units (plants) are analysed without having to inspect individual plants. However, when using group testing we need to consider an appropriate pool size (k) because if the k individuals that form a pool are mixed and homogenized, the AP will be diluted. This effect increases with the size of the pool; it may also decrease the AP concentration in the pool below the laboratory test detection limit (d), thereby increasing the number of false negatives. The method proposed in this study determines the required sample size considering the dilution effect and guarantees narrow confidence intervals. In addition, we derived the maximum likelihood estimator of p and an exact confidence interval (CI) under negative binomial pool testing considering the detection limit of the laboratory test, d, and the concentration of AP per unit (c). Simulated data were created and tables presented showing different potential scenarios that a researcher may encounter. We also provide an R program that can be used to create other scenarios.

Application of Receiver Operating Characteristic Analysis to Refine the Prediction of Potential Digoxin Drug Interactions

In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC₅₀ ([I₁]/IC₅₀) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC₅₀ ([I₂]/IC₅₀) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC₅₀ values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC₅₀ values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I₁]/IC₅₀ ≥ 0.03 and [I₂]/IC₅₀ ≥ 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC₅₀ values, a theoretical 95% confidence interval calculation was developed for single laboratory IC₅₀ values, translating into a range of [I₁]/IC₅₀ and [I₂]/IC₅₀ values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC₅₀ values.