Number Of False-positive Results Research Articles

Abstract 234: Computational characterization of microRNA-mediated association between obesity and cancer

Abstract MicroRNAs control gene expression in many fundamental cellular processes that are associated with pathogenesis of human cancer and obesity. However, the microRNA-mediated association between cancer and obesity is largely under-investigated, in spite of the emerging evidences indicating 1) a higher risk of pancreatic cancer and breast cancer in obese people 2) a novel mechanism to understand the links, e.g. upregulation of insulin-like growth factor-1 (IGF-1) in overweight individuals may promote pancreatic cancer 3) IGF-1 regulation of tumor suppressive miRNAs such as miR-15b, miR-98, miR-195, miR-200b, let-7c and let-7g. Based on limited knowledge of the relationship between obesity and cancer, we have applied an omics-driven integrative approach to systematically study the regulatory role of microRNA in cancer and obesity and to elucidate the association between these two types of diseases from the microRNA regulation perspective. Specifically, we have collected large-scale genomics data on obesity and three types of cancer, namely, pancreatic cancer, gastric cancer and ovarian cancer in this analysis. Given the fact that most of current methodologies for microRNA target prediction are largely dependent on computational identification of the static binding sites on mRNAs according to the sequence and structural features, they often produce a considerable number of false positive results. To tackle this problem, we have developed a new approach for identifying microRNA-mRNA interactions using sophisticated bioinformatics techniques in cooperation with genomics information. The dynamic binding feature has been taken into consideration, which integrates both cooperative and competitive manners of microRNA-mRNA binding in human. Our analysis has identified a list of obesity-associated microRNAs, part of which shows strong association with cancers under investigation. Through our new target prediction, a few such disease-related microRNAs are found to participate in various metabolic processes, such as cellular acetyl-CoA and lipid metabolism pathway (e.g. miR-103, miR-200a, miR-30c and miR-107) and cancer pathways (e.g. miR-519, miR-27a/b, miR-96 and miR-143) through regulating their targets. Moreover, we have discovered alterations of the microRNA-mRNA interaction network across cancer progression through dynamic modeling. Overall, we demonstrates such integrative study using computational modeling and omics information can effectively facilitate the discovery of disease-related microRNA regulation network and bring new insights into understanding of the association between obesity and cancer. Citation Format: Jiang Shu, Kevin Chiang, Juan Cui. Computational characterization of microRNA-mediated association between obesity and cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 234. doi:10.1158/1538-7445.AM2015-234

MR Imaging as an Additional Screening Modality for the Detection of Breast Cancer in Women Aged 50-75 Years with Extremely Dense Breasts: The DENSE Trial Study Design.

Women with extremely dense breasts have an increased risk of breast cancer and lower mammographic tumor detectability. Nevertheless, in most countries, these women are currently screened with mammography only. Magnetic resonance (MR) imaging has the potential to improve breast cancer detection at an early stage because of its higher sensitivity. However, MR imaging is more expensive and is expected to be accompanied by an increase in the number of false-positive results and, possibly, an increase in overdiagnosis. To study the additional value of MR imaging, a randomized controlled trial (RCT) design is needed in which one group undergoes mammography and the other group undergoes mammography and MR imaging. With this design, it is possible to determine the proportion of interval cancers within each study arm. For this to be an effective screening strategy, the additional cancers detected at MR imaging screening must be accompanied by a subsequent reduction in interval cancers. The Dense Tissue and Early Breast Neoplasm Screening, or DENSE, trial is a multicenter RCT performed in the Dutch biennial population-based screening program (subject age range, 50-75 years). The study was approved by the Dutch Minister of Health, Welfare and Sport. In this study, mammographic density is measured by using a fully automated volumetric method. Participants with extremely dense breasts (American College of Radiology breast density category 4) and a negative result at mammography (Breast Imaging Recording and Data System category 1 or 2) are randomly assigned to undergo additional MR imaging (n = 7237) or to be treated according to current practice (n = 28 948). Participants provide written informed consent before the MR imaging examination, which consists of dynamic breast MR imaging with gadolinium-based contrast medium and is intended to be performed for three consecutive screening rounds. The primary outcome is the difference in the proportions of interval cancers between the study arms. Secondary outcomes are the number of MR imaging screening-detected cancers, proportions of false-positive results, diagnostic yield of MR imaging, tumor characteristics, quality of life, and cost effectiveness.

Qualitative visual trichotomous assessment improves the value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in predicting the prognosis of diffuse large B-cell lymphoma.

IntroductionFluorine-18 fluorodeoxyglucose (18 F-FDG) positron emission tomography/computed tomography (PET/CT) is a powerful tool for monitoring the response of diffuse large B-cell lymphoma (DLBCL) to therapy, but the criteria to interpret PET/CT results remain under debate. We investigated the value of post-treatment PET/CT in predicting the prognosis of DLBCL patients when interpreted according to qualitative visual trichotomous assessment (QVTA) criteria compared with the Deauville criteria.MethodsIn this retrospective study, final PET/CT scans of DLBCL patients treated with rituximab-based regimens between October 2005 and November 2010 were interpreted using the Deauville and QVTA criteria. Survival curves were estimated using Kaplan-Meier analysis and compared using the log-rank test.ResultsA total of 253 patients were enrolled. The interpretation according to the Deauville criteria revealed that 181 patients had negative PET/CT scan results and 72 had positive results. The 3 year overall survival (OS) rate was significantly higher in patients with negative scan results than in those with positive results (91.6 % vs. 57.5 %, P < 0.001). The 72 patients with positive scan results according to the Deauville criteria were divided into two groups by the interpretation according to the QVTA criteria: 29 had indeterminate results, and 43 had positive results. The 3 year OS rate was significantly higher in patients with indeterminate scan results than in those with positive results (91.2 % vs. 33.5 %, P < 0.001) but was similar between patients with negative and indeterminate scan results (91.6 % vs. 91.2 %, P = 0.921).ConclusionsCompared with the Deauville criteria, using the QVTA criteria for interpreting post-treatment PET/CT scans of DLBCL patients is likely to reduce the number of false positive results. The QVTA criteria are feasible for therapeutic outcome evaluation and can be used to guide risk-adapted therapy.

Diabetes mellitus, obesity and chronic pancreatitis? Independent risk factors for pancreatic adenocarcinoma (PAC) in Romanian Black Sea coast area

Patients & methods: Prospective diagnostic accuracy study in a tertiary HPB center according to the STARD guidelines. We included patients undergoing pancreatoduodenectomy or radiofrequency ablation (RFA) combined with bypass surgery. Extra-regional lymph nodes were defined as lymph nodes in the aortocaval window. An expert HPB-radiologist prospectively assessed aortocaval lymph nodes on preoperative CT according to a standardized protocol. All tissue from the aortocaval window was harvested intra-operatively. The reference test was histopathology. Results: Between March 2013 and December 2014, 77 consecutive patients were included. In 69 patients (90%) a pancreatoduodenectomy was performed and 8 patients underwent RFA (n1⁄47) or only bypass (n1⁄41). A median of 3 aortocaval lymph nodes(IQR 1-4) were harvested per patient. Nine patients (12%) had aortocaval LNM. Negative predictive value of CT in assessing aortocaval LNM was 88%(95%CI 77-94%) and positive predictive value was 10%(CI 1-46%). Overall diagnostic accuracy was 22%. Conclusion: CT has a low diagnostic accuracy in assessing extraregional LNM in pancreatic or peri-ampullary cancer, mainly due to the high number of false positive results. Signs of aortocaval LNM on CT should therefore not be a contra-indication for surgical exploration or other treatments that are part of a strategy with curative intent.

Laboratory procedures update on Hirschsprung disease.

The detection of ganglion cells in rectal biopsies of infants or toddlers with severe constipation is routinely performed by pediatric pathologists in many institutions. Hirschsprung disease (HD) is defined by the lack of ganglion cells (aganglionosis). The early recognition and the prompt implementation of surgical procedures obviously protect infants affected with HD from potential life-threatening conditions, including enterocolitis and debilitating constipation. Image-based and non-image-based clinical techniques and some laboratory tests have been reevaluated along the years, but often fragmentarily. Immunohistochemical markers have been increasingly used in pathology laboratories to detect ganglion cells and nerve fibers. Recently, calretinin, a vitamin D-dependent calcium-binding protein with expression in ganglion cells and nerves, has been described as an adjunctive or primary diagnostic test in HD. The aim of the present study was to systematically summarize and update laboratory procedures targeting ganglion cells in rectal biopsies. Procedures and tests have been reviewed and values of specificity and sensitivity have been calculated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Contrast enema has the lowest sensitivity and specificity of all of the 3-index investigations under the lens: contrast enema, anorectal manometry, and biopsy with histology. The latter procedure seems to have the highest sensitivity and specificity. Acetylcholinesterase staining on fresh-frozen material has been found to have slightly higher rates of sensitivity and specificity when compared with hematoxylin and eosin only. Calretinin staining may be supportive for the diagnosis, although some cases with false-positivity may be of some concern. Hematoxylin and eosin with or without acetylcholinesterase remains the criterion standard according to our PRISMA-based data. In our opinion, the number of false-positive results with potential overtreatment may limit the increasing advocacy for calretinin staining. Both the "primum non nocere" dictum and the "loss aversion heuristic" need to be satisfied harmoniously by preventing harm from unnecessary surgery.

Comparison of Nonstress Test and Light stimulation Test and their correlation with fetal outcome

Introduction: Non Stress Test serves an important function in assessment of fetal wellbeing, but false positive results limit its role. Light stimulation stimulates the fetus, speeds up the test and catalyses its rate limiting step. This study has compared simple Non Stress Test and Light stimulation test and there correlation with various fetal outcomes. This study helps us to assess whether light stimulation be used as a better alternative or an adjunct to traditional Nonstress test. Material and Methods: A total of 220 patients above 34 weeks of pregnancy were taken.110 pts underwent 20 minutes of Nonstress test and 110 underwent Halogen light stimulation which was given transabdominally for 10 seconds and it was repeated every 10 minutes for a maximum up to three times. This allocation was done randomly. Non reactive Nonstress test were then stimulated with Halogen light . Results : The test showed that sensitivity of Nonstress test is greater than Light stimulation test, but specificity, positive predictive value, and negative predictive value is lesser than Light stimulation test .Out of 36 Non reactive NSTs after stimulation with light 18 became reactive. Conclusion Nonstress test is considered as a screening test and Light stimulation test can be used as an adjunct to Nonstress test as it decreases the number of false positive results and increases the specificity of the test. Clinical outcomes are more closely related with LST, but more studies are required to arrive at the final conclusions.

Newborn Screening for Severe Combined Immunodeficiency (SCID) in Ohio: Using Algorithms to Standardize Follow-up Limits the Number of False Positive Results

T cell receptor excision circle (TREC) analysis on newborn screening (NBS) dried blood spot specimens has proven to be a successful method of screening for Severe Combined Immunodeficiency (SCID). We hypothesized that standardized algorithms for follow-up of abnormal values would decrease the number of false positives results.

Formation of a carbapenemase resistance detection algorithm for use in the routine laboratory

ABSTRACTThe increasing prevalence of carbapenem non-susceptible Gram negative organisms demands prompt and accurate identification of resistance mechanisms to limit their transmission. The aim of this study is to evaluate the rapid CARB screen (Rosco Diagnostica, Denmark), the ‘KPC/MBL in P. aeruginosa/Acinetobacter Confirm Kit’ (Rosco Diagnostica), Check-MDR Carba and Check-Direct CPE kits (Check-Points, The Netherlands). The purpose of this study is the formation of a carbapenemase resistance detection algorithm that can be used in the routine laboratory. Results of the rapid CARB screen kit were improved when isolates were tested from Muller Hinton agar with a meropenem 10 μg disc instead of blood agar. The rapid CARB screen (performed in 2–3 h) demonstrated overall 98.7% sensitivity and 87.7% specificity (n=133). The KPC/MBL in P. aeruginosa/Acinetobacter Confirm Kit (which requires overnight incubation) demonstrated a high number of false-positive results giving 38.6% specificity and 100% sensitivity (n=44). The Check-MDR Carba (performed in 5 h), detecting carbapenemase presence, provides a cabapenemase-positive or -negative result demonstrated 96.7% specificity and 98.6% sensitivity (n = 132). The Check-Direct CPE (performed in 3 h), which identifies KPC, NDM/VIM or OXA-48 type carbapenemases, demonstrated 96.5% specificity and 97.1% sensitivity (n=97). The Check-Direct CPE, however, failed to detect dual carbapenemase genes present in two out of four isolates. The principal conclusion is the recommendation of the rapid CARB screen and Check-MDR Carba for incorporation into a carbapenemase detection algorithm which, when used in combination, will yield results with 97.3% sensitivity and 99.6% specificity.

Prospective Evaluation of MRI and PET-CT at Diagnosis and before Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in the IFM/DFCI 2009 Trial

IntroductionMagnetic resonance imaging (MRI) of the spine and the pelvis is an important tool to evaluate bone disease in patients with symptomatic multiple myeloma (MM) at the time of diagnosis. In the context of high-dose therapy and autologous stem cell transplantation (ASCT), it has also been reported that the number of MRI focal lesions (> 7) and the presence of diffuse pattern correlate with inferior survival (Walker et al. J Clin Oncol; 25:1121-1128 2007). MRI might help in the better definition of complete response (CR). However, the high number of false positive results suggests that another imaging method, such as Positron emission tomography combined with computed tomography using fluoro-deoxy-glucose (PET-CT), might be of more value in this setting. Moreover, imaging techniques have rarely been compared to minimal residual disease (MRD) evaluated by flow cytometry from bone marrow aspiration in the context of frontline therapy including novel agents and ASCT. The goal of our study was to compare prospectively MRI and PET-CT at 3 different time-points, at diagnosis, after 3 cycles of triplet induction therapy and prior to maintenance therapy in a group of patients enrolled into IFM-DFCI 2009 trial comparing frontline or delayed ASCT.Patients and methodsIn the prospective IFM-DFCI 2009 trial, 700 patients with de novo symptomatic MM eligible for high-dose therapy have been randomized in France and Belgium to receive either 8 cycles of bortezomib-lenalidomide-dexamethasone (VRD) followed by 1-year maintenance with lenalidomide, or 3 cycles of VRD followed by high-dose therapy and ASCT plus 2 cycles of VRD consolidation and 1-year lenalidomide maintenance. 134 / 700 patients were also included in the IMAJEM trial (NCT01309334, also supported by STIC program granted by the French NCI) aimed at comparing in both arms of the IFM-DFCI 2009 study spine and pelvis MRI and whole-body PET-CT at diagnosis (number of lesions, primary end-point), after 3 cycles of VRD, and prior to maintenance (prognosis impact of imaging negativity, secondary end-point). PET-CT and MRI results before maintenance were also compared with MRD assessed by 8-color flow cytometry. MRI and PET-CT data were analyzed locally in each of the 15 participating centers, and systematically reviewed blindly by an independent committee consisting of 2 radiologists and 2 nuclear medicine physicians with extensive experience in MM field.ResultsAt diagnosis, MRI was positive in 127/134 (94.7%), and PET-CT in 122/134 (91%) patients, respectively (McNemar test = 0.94, p-value = 0.33). MRI patterns of marrow involvement were the following: (1) normal in 7 cases (5%); (2) focal lesions (FL) in 46 cases (34%); (3) homogeneous diffuse infiltration in 41 cases (31%); (4) combined diffuse infiltration and FL in 35 cases (26%); and (5) variegated or "salt-and-pepper" pattern with inhomogeneous bone marrow with interposition of fat islands in 5 cases (4%). PET-CT patterns were the following: (1) normal in 12 cases (9%); (2) FL in 44 cases (33%); (3) diffuse infiltration in 12 cases (9%); (4) combined diffuse infiltration and FL in 66 cases (49%); (5) extramedullary disease in 10 cases (7.5%). The median number of FL assessed by PET-CT was 3.ConclusionMRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis. The prognosis relevance of both MRI and PET-CT, and the comparison with MRD assessed by flow cytometry will be presented at the meeting. DisclosuresKarlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Stoppa:Janssen: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hulin:Celgene Corporation: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.

Uncertain Reasoning for Detection of Selling Stolen Goods in Online Auctions Using Contextual Information

This work describes the design of a decision support system for detection of fraudulent behavior of selling stolen goods in online auctions. In this system, each seller is associated with a type of certification, namely “proper seller,” “suspect seller,” and “selling stolen goods.” The certification level is determined on the basis of a seller’s behaviors and especially on the basis of contextual information whose origin is outside online auctions portals. In this paper, we focus on representing knowledge about sellers in online auctions, the influence of additional information available from other Internet source, and reasoning on bidders’ trustworthiness under uncertainties using Dempster-Shafer theory of evidence. To demonstrate the practicability of our approach, we performed a case study using real auction data from Czech auction portal Aukro. The analysis results show that our approach can be used to detect selling stolen goods. By applying Dempster-Shafer theory to combine multiple sources of evidence for the detection of this fraudulent behavior, the proposed approach can reduce the number of false positive results in comparison to approaches using a single source of evidence.

PS-288 The Performance Of Imaging For Suspected Malrotation: Not So Bad After All

Despite reports of imaging characteristics that would identify intestinal rotational anomalies that predispose to volvulus, most paediatric surgeons would proceed to an operation when imaging is suggestive. The aim of this study was to test the performance of the upper gastrointestinal (UGI) contrast studies and its restrictions that lead to false positive or false negative reports. Methods We performed a retrospective analysis of patients investigated for malrotation, or treated for it over 5 years (2008–2013). Radiology reports were graded as positive, equivocal or negative. If the study was inconclusive, further imaging or treatment was dictated by clinical status. Main Results 279 patients were investigated due to suspected malrotation, while in 24 patients malrotation was an incidental finding. In total, 86 patients underwent a Ladd’s procedure. If the definite positive and equivocal reports were considered as positive regarding the intention to intervene surgically, the sensitivity of UGIS was 94%, specificity was 95.4%, with 18% false positive results and 1.4% false negatives. In the 11 patients with proven false positive results, two had a negative laparotomy, but all the remaining 9 patients had surgical findings (including 3 duodenal stenoses, and 3 intestinal atresias). Conclusion The UGI series proved to be very sensitive and specific for the diagnosis of malrotation, when the clinical pathway dictates prompt surgical intervention in the presence of positive or at least non-negative radiology report. This approach can lead to a significant number of false positive results, although other surgically treatable pathology is commonly identified in these patients.

Calculation of limits for significant bidirectional changes in two or more serial results of a biomarker based on a computer simulation model.

Reference change values provide objective tools to assess the significance of a change in two consecutive results of a biomarker from an individual. However, in practice, more results are usually available and using the reference change value concept on more than two results will increase the number of false positive results. A computer simulation model was developed using Excel. Based on 10,000 simulated measurements among healthy individuals, a series of up to 20 results of a biomarker from each individual was generated using different values for the within-subject biological variation plus the analytical variation. Each new result in this series was compared to the initial result. These successive serial differences were computed to give limits for significant bidirectional changes with constant cumulated maximum probabilities of 95% (p < 0.05) and 99% (p < 0.01). From an individual factors used to multiply the first result were calculated to create limits for constant cumulated significant changes. The factors were shown to become a function of the number of results included and the total coefficient of variation. The first result should be multiplied by the appropriate factors for increase and decrease to give the limits for a significant bidirectional change in several consecutive measurements.

HPV and cervical cancer

In recent analyses of the global burden of cancer among women, cervical cancer ranked second to breast cancer. Numbers of new cervical cancer cases are increasing constantly although this tumor is one of the best preventable malignancies of all relevant human cancers. The genesis of cervical cancer depends essentially on an infection of the uterine cervix with human papillomavirus (HPV) that needs to persist for many years and decades. Oncogenic cell transformation occurs almost exclusively in a discrete cell population at the squamous columnar junction (SCJ). These peculiarities enable primary prevention with HPV-vaccination as well as secondary prevention by detecting and treating true precursor lesions.The actual screening program with annual cytology smears is already effective but results in a high number of false positive results and unnecessary treatments. Based on a good understanding of the etiology and high evidence from large randomized controlled trials a significant improvement in the prevention of cervical cancer by shifting to HPV screening in women aged 30 years or older is feasible. This would result in a further reduction of new cancer cases by 70–80 % with less screening examinations and interventions when well-defined patient pathways are followed and colposcopy in accordance with international quality standards is used as the gold standard for the minimal invasive management of abnormal findings. HPV vaccination prevents the development of approximately 80 % of true precursors and should have a similar impact on the incidence of cervical cancer. A combination of HPV vaccination and screening could almost eradicate cervical cancer and reduce the burden of other tumors and diseases related to HPV.

Nucleic acid amplification tests for the diagnosis of Neisseria gonorrhoeae in low-prevalence settings: a review of the evidence

ObjectivesIn UK Microbiology laboratories there is widespread use of nucleic acid amplification tests (NAATs) which allow the simultaneous ‘dual’ detection of Neisseria gonorrhoeae and Chlamydia trachomatis, although the prevalence of...

False-positive rates in two-point parametric linkage analysis.

Two-point linkage analyses of whole genome sequence data are a promising approach to identify rare variants that segregate with complex diseases in large pedigrees because, in theory, the causal variants have been genotyped. We used whole genome sequence data and simulated traits provided by Genetic Analysis Workshop 18 to evaluate the proportion of false-positive findings in a binary trait using classic two-point parametric linkage analysis. False-positive genome-wide significant log of odds (LOD) scores were identified in more than 80% of 50 replicates for a binary phenotype generated by dichotomizing a quantitative trait that was simulated with a polygenic component (that was not based on any of the provided whole genome sequence genotypes). In contrast, when the trait was truly nongenetic (created by randomly assigning affected-unaffected status), the number of false-positive results was well controlled. These results suggest that when using two-point linkage analyses on whole genome sequence data, one should carefully examine regions yielding significant two-point LOD scores with multipoint analysis and that a more stringent significance threshold may be needed.

False discovery rate control in magnetic resonance imaging studies via Markov random fields.

Magnetic resonance imaging (MRI) is widely used to study population effects of factors on brain morphometry. Inference from such studies often require the simultaneous testing of millions of statistical hypotheses. Such scale of inference is known to lead to large numbers of false positive results. Control of the false discovery rate (FDR) is commonly employed to mitigate against such outcomes. However, current methodologies in FDR control only account for the marginal significance of hypotheses, and are not able to explicitly account for spatial relationships, such as those between MRI voxels. In this article, we present novel methods that incorporate spatial dependencies into the process of controlling FDR through the use of Markov random fields. Our method is able to automatically estimate the relationships between spatially dependent hypotheses by means of maximum pseudo-likelihood estimation and the pseudo-likelihood information criterion. We show that our methods have desirable statistical properties with regards to FDR control and are able to outperform noncontexual methods in simulations of dependent hypothesis scenarios. Our method is applied to investigate the effects of aging on brain morphometry using data from the PATH study. Evidence of whole brain and component level effects that correspond to similar findings in the literature is found in our investigation.

Reprint of “Influence of analytical bias and imprecision on the number of false positive results using Guideline-Driven Medical Decision Limits”

BackgroundDiagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions due to the strict dichotomization of patients into diseased and non-diseased. Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where much other information is included. The aim of this opinion paper is to investigate consequences of analytical quality and other circumstances for the outcome of “Guideline-Driven Medical Decision Limits”. TermsEffects of analytical bias and imprecision should be investigated separately and analytical quality specifications should be estimated accordingly. Biological variation and analytical performanceUse of sharp decision limits doesn't consider biological variation and effects of this variation are closely connected with the effects of analytical performance. Such relationships are investigated for the guidelines for HbA1c in diagnosis of diabetes and in risk of coronary heart disease based on serum cholesterol. The effects of a second sampling in diagnosis give dramatic reduction in the effects of analytical quality showing minimal influence of imprecision up to 3 to 5% for two independent samplings, whereas the reduction in bias is more moderate and a 2% increase in concentration doubles the percentage of false positive diagnoses, both for HbA1c and cholesterol. Frequency of follow-up laboratory testsAn alternative approach comes from the current application of guidelines for follow-up laboratory tests according to clinical procedure orders, e.g. frequency of parathyroid hormone requests as a function of serum calcium concentrations. Here, the specifications for bias can be evaluated from the functional increase in requests for increasing serum calcium concentrations. Probability function for diagnosesIn consequence of the difficulties with biological variation and the practical utilization of concentration dependence of frequency of follow-up laboratory tests already in use, a kind of probability function for diagnosis as function of the key-analyte is proposed.

Biochemical and radiological relationships in patients with pheochromocytoma: lessons from a case control study

An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest. To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines. We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines ≥4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3. The median (range) tumour size in group 1 and group 2 was 4·8 cm (1·7-22) and 3·0 cm (1·7-5) respectively (P < 0·001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre-contrast attenuation ≥17 Hounsfield Units (HU). Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU.

Re-evaluation of microscopy confirmed Plasmodium falciparum and Plasmodium vivax malaria by nested PCR detection in southern Ethiopia

BackgroundWith 75% of the Ethiopian population at risk of malaria, accurate diagnosis is crucial for malaria treatment in endemic areas where Plasmodium falciparum and Plasmodium vivax co-exist. The present study evaluated the performance of regular microscopy in accurate identification of Plasmodium spp. in febrile patients visiting health facilities in southern Ethiopia.MethodsA cross-sectional study design was employed to recruit study subjects who were microscopically positive for malaria parasites and attending health facilities in southern Ethiopia between August and December 2011. Of the 1,416 febrile patients attending primary health facilities, 314 febrile patients, whose slides were positive for P. falciparum, P. vivax or mixed infections using microscopy, were re-evaluated for their infection status by PCR. Finger-prick blood samples were used for parasite genomic DNA extraction. Phylogenetic analyses were performed to reconstruct the distribution of different Plasmodium spp. across the three geographical areas.ResultsOf the 314 patients with a positive thick blood smear, seven patients (2%) were negative for any of the Plasmodium spp. by nested PCR. Among 180 microscopically diagnosed P. falciparum cases, 111 (61.7%) were confirmed by PCR, 44 (24.4%) were confirmed as P. vivax, 18 (10%) had mixed infections with P. falciparum and P. vivax and two (1.1%) were mixed infections with P. falciparum and P. malariae and five (2.8%) were negative for any of the Plasmodium spp. Of 131 microscopically diagnosed P. vivax cases, 110 (84%) were confirmed as P. vivax, 14 (10.7%) were confirmed as P. falciparum, two (1.5%) were P. malariae, three (2.3%) with mixed infections with P. falciparum and P. vivax and two (1.5%) were negative for any of the Plasmodium spp. Plasmodium falciparum and P. vivax mixed infections were observed. Plasmodium malariae was detected as mono and mixed infections in four individuals.ConclusionFalse positivity, under-reporting of mixed infections and a significant number of species mismatch needs attention and should be improved for appropriate diagnosis. The detection of substantial number of false positive results by molecular methodologies may provide the accurate incidence of circulating Plasmodium species in the geographical region and has important repercussions in understanding malaria epidemiology and subsequent control.

A simple and rapid screening method for sulfonamides in honey using a flow injection system coupled to a liquid waveguide capillary cell

A rapid and simple screening method was developed for the determination of sulfonamides in honey samples by flow injection analysis (FIA) coupled to a liquid waveguide capillary cell. The proposed method is based on the reaction between sulfonamides and p-dimethylaminocinnamaldehyde (p-DAC) in the presence of sodium dodecylsulate (SDS) in dilute acid medium (hydrochloric acid), with the reaction product being measured spectrophotometrically at λ(max) = 565 nm. Experimental design methodology was used to optimize the analytical conditions. The proposed technique was applied to the determination of sulfonamides (sulfaquinoxaline, sulfadimethoxine, and sulfathiazole) in honey samples, in a concentration range from 6.00 × 10(-3) to 1.15 × 10(-1)mg L(-1). The detection (LOD) and quantification (LOQ) limits were 1.66 × 10(-3) and 5.54 × 10(-3)mg L(-1), respectively. Positive and false positive samples were also analyzed by a confirmatory HPLC method. The proposed system enables the screening of sulfonamides in honey samples with a low number of false positive results, with fast response therefore offers a new tool for consumer protection.