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False Positive Rate (false + positive_rate)
Kinds of False Positive Rate Selected AbstractsWhy do primary care doctors diagnose depression when diagnostic criteria are not met?INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH, Issue 3 2000Michael Höfler Abstract This study examines predictors of false positive depression diagnoses by primary care doctors in a sample of primary care attendees, taking the patients' diagnostic status from a self-report measure (Depression Screening Questionnaire, DSQ) as a yardstick against which to measure doctors' correct and false positive recognition rates. In a nationwide study, primary care patients aged 15,99 in 633 doctors' offices completed a self-report packet that included the DSQ, a questionnaire that assesses depression symptoms on a three-point scale to provide diagnoses of depression according to the criteria of DSM-IV and ICD-10. Doctors completed an evaluation form for each patient seen, reporting the patient's depression status, clinical severity, and treatment choices. Predictor analyses are based on 16,909 patient-doctor records. Covariates examined included depression symptoms, the total DSQ score, number and persistence of depression items endorsed, patient's prior treatment, history of depression, age and gender. According to the DSQ, 11.3% of patients received a diagnosis of ICD-10 depression, 58.9% of which were correctly identified by the doctor as definite threshold, and 26.2% as definite subthreshold cases. However, an additional 11.7% of patients not meeting the minimum DSQ threshold were rated by their doctors as definitely having depression (the false positive rate). Specific DSQ depression items endorsed, a higher DSQ total score, more two-week depression symptoms endorsed, female gender, higher age, and patient's prior treatment were all associated with an elevated rate of false positive diagnoses. The probability of false positive diagnoses was shown to be affected more by doctors ignoring the ,duration of symptoms' criterion than by doctors not following the ,number of symptoms' criterion for an ICD or DSM diagnosis of depression. A model selection procedure revealed that it is sufficient to regress the ,false positive diagnoses' on the DSQ-total score, symptoms of depressed mood, loss of interest, and suicidal ideation; higher age; and patient's prior treatment. Further, the total DSQ score was less important in prediction if there was a prior treatment. The predictive value of this model was quite good, with area under the ROC-curve = 0.86. When primary care doctors use depression screening instruments they are oversensitive to the diagnosis of depression. This is due to not strictly obeying the two weeks duration required by the diagnostic criteria of ICD-10 and DSM-IV. False positive rates are further increased in particular by the doctor's knowledge of a patient's prior treatment history as well as the presence of a few specific depression symptoms. Copyright © 2000 Whurr Publishers Ltd. [source] Detecting New Forms of Network Intrusion Using Genetic ProgrammingCOMPUTATIONAL INTELLIGENCE, Issue 3 2004Wei Lu How to find and detect novel or unknown network attacks is one of the most important objectives in current intrusion detection systems. In this paper, a rule evolution approach based on Genetic Programming (GP) for detecting novel attacks on networks is presented and four genetic operators, namely reproduction, mutation, crossover, and dropping condition operators, are used to evolve new rules. New rules are used to detect novel or known network attacks. A training and testing dataset proposed by DARPA is used to evolve and evaluate these new rules. The proof of concept implementation shows that a rule generated by GP has a low false positive rate (FPR), a low false negative rate and a high rate of detecting unknown attacks. Moreover, the rule base composed of new rules has high detection rate with low FPR. An alternative to the DARPA evaluation approach is also investigated. [source] Comparison of bone marrow and peripheral blood ZAP-70 status examined by flow cytometric immunophenotyping in patients with chronic lymphocytic leukemiaCYTOMETRY, Issue 4 2006Rachel Sheridan Abstract Background: The mutational status of the immunoglobulin heavy chain variable gene in patients with chronic lymphocytic leukemia correlates with prognosis. Patients with mutated IgVH genes fare better than those with unmutated genes. Gene expression profiling studies identified the tyrosine kinase ZAP-70 to be expressed in unmutated CLL samples. Flow cytometric examination of ZAP-70 expression in tumor cells has been proposed to be a convenient surrogate marker for IgVH mutational status. However, a few studies have shown a small number of discordant results between ZAP-70 positivity, IgVH mutational status, and clinical outcome. There have been no reported studies comparing bone marrow samples with peripheral blood for ZAP-70 expression in CLL patients. Methods: We searched our flow cytometry files from October 2004 through April 2006 and identified CLL in 311 bone marrow and peripheral blood specimens from 256 patients. We defined ZAP-70 positivity as greater than 30% of the CD19+ B-cells above the isotype control value that coexpress ZAP-70. Statistical analyses were performed using the Fisher exact test and student t -test. Results: A significantly greater number of bone marrow specimens were positive for ZAP-70 when compared with the number of peripheral blood specimens. Of all the ZAP-70 negative specimens, CLL cells from bone marrow had a greater mean percentage of ZAP-70 positive cells when compared with the CLL cells from peripheral blood. Finally, six patients were identified who were ZAP-70 positive in the bone marrow but ZAP-70 negative in the peripheral blood. Conclusions: These results may be due to either an increase in the false positive rate in bone marrow specimens or to an intrinsic feature of CLL cells in the compartment that is biologically distinct from peripheral tumor cells. As prognosis and treatment decisions may be based on ZAP-70 results from either specimen type, it is prudent to further examine this observation. © 2006 International Society for Analytical Cytology [source] Making the case for objective performance metrics in newborn screening by tandem mass spectrometryDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 4 2006Piero Rinaldo Abstract The expansion of newborn screening programs to include multiplex testing by tandem mass spectrometry requires understanding and close monitoring of performance metrics. This is not done consistently because of lack of defined targets, and interlaboratory comparison is almost nonexistent. Between July 2004 and April 2006 (N = 176,185 cases), the overall performance metrics of the Minnesota program, limited to MS/MS testing, were as follows: detection rate 1:1,816, positive predictive value 37% (54% in 2006 till date), and false positive rate 0.09%. The repeat rate and the proportion of cases with abnormal findings actually been reported are new metrics proposed here as an objective mean to express the overall noise in a program, where noise is defined as the total number of abnormal results obtained using a given set of cut-off values. On the basis of our experience, we propose the following targets as evidence of adequate analytical and postanalytical performance: detection rate 1:3,000 or higher, positive predictive value >20%, and false positive rate <0.3%. © 2006 Wiley-Liss, Inc. MRDD Research Reviews 2006;12:255,261. [source] Atypical papillary proliferation in gynecologic patients: A study of 32 pelvic washes,DIAGNOSTIC CYTOPATHOLOGY, Issue 2 2005Karyna C. Ventura M.D. Abstract Papillary clusters in gynecologic pelvic washes frequently cause diagnostic challenges because they can be associated with borderline or malignant ovarian tumors, as well as benign pelvic diseases. The objective of our study was to review all pelvic washes with atypical papillary proliferation (APP) and investigate whether cytomorphology and/or immunohistochemistry on cell block could determine their origin. Thirty-two pelvic washes from 31 patients containing APP were reviewed and correlated with their corresponding gynecologic or pelvic disease. Previously obtained cell blocks with immunohistochemical (IHC) stains were reviewed also. Nine of 32 washes (28%) were overcalled as malignant and were from patients with 5 borderline serous ovarian tumors (BSTO), 1 ovarian follicular cyst, 1 serous cystadenofibroma, and 1 endometrial carcinoma with ovarian seromucinous cystadenoma. BSTO and endometriosis were the most common sources of APP. Cell blocks could not discriminate further the etiology of APP. Immunohistochemistry was performed rarely and not fully contributory. Caution in interpreting papillary groups and cytohistological correlation is recommended to prevent a high false positive rate. Diagn. Cytopathol. 2005;32:76,81. © 2005 Wiley-Liss, Inc. [source] Applications and statistical properties of minimum significant difference-based criterion testing in a toxicity testing program,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2000Qin Wang Abstract As a follow up to the recommendations of the September 1995 SETAC Pellston Workshop on Whole Effluent Toxicity (WET) on test methods and appropriate endpoints, this paper will discuss the applications and statistical properties of using a statistical criterion of minimum significant difference (MSD). We examined the upper limits of acceptable MSDs as acceptance criterion in the case of normally distributed data. The implications of this approach are examined in terms of false negative rate as well as false positive rate. Results indicated that the proposed approach has reasonable statistical properties. Reproductive data from short-term chronic WET test with Ceriodaphnia dubia tests were used to demonstrate the applications of the proposed approach. The data were collected by the North Carolina Department of Environment, Health, and Natural Resources (Raleigh, NC, USA) as part of their National Pollutant Discharge Elimination System program. [source] Detecting intrusion transactions in databases using data item dependencies and anomaly analysisEXPERT SYSTEMS, Issue 5 2008Sattar Hashemi Abstract: The purpose of the intrusion detection system (IDS) database is to detect transactions that access data without permission. This paper proposes a novel approach to identifying malicious transactions. The approach concentrates on two aspects of database transactions: (1) dependencies among data items and (2) variations of each individual data item which can be considered as time-series data. The advantages are threefold. First, dependency rules among data items are extended to detect transactions that read or write data without permission. Second, a novel behaviour similarity criterion is introduced to reduce the false positive rate of the detection. Third, time-series anomaly analysis is conducted to pinpoint intrusion transactions that update data items with unexpected pattern. As a result, the proposed approach is able to track normal transactions and detect malicious ones more effectively than existing approaches. [source] Centralizing the non-central chi-square: a new method to correct for population stratification in genetic case-control association studiesGENETIC EPIDEMIOLOGY, Issue 4 2006Prakash Gorroochurn Abstract We present a new method, the ,-centralization (DC) method, to correct for population stratification (PS) in case-control association studies. DC works well even when there is a lot of confounding due to PS. The latter causes overdispersion in the usual chi-square statistics which then have non-central chi-square distributions. Other methods approach the non-centrality indirectly, but we deal with it directly, by estimating the non-centrality parameter , itself. Specifically: (1) We define a quantity ,, a function of the relevant subpopulation parameters. We show that, for relatively large samples, , exactly predicts the elevation of the false positive rate due to PS, when there is no true association between marker genotype and disease. (This quantity , is quite different from Wright's FST and can be large even when FST is small.) (2) We show how to estimate ,, using a panel of unlinked "neutral" loci. (3) We then show that ,2 corresponds to , the non-centrality parameter of the chi-square distribution. Thus, we can centralize the chi-square using our estimate of ,; this is the DC method. (4) We demonstrate, via computer simulations, that DC works well with as few as 25,30 unlinked markers, where the markers are chosen to have allele frequencies reasonably close (within ±.1) to those at the test locus. (5) We compare DC with genomic control and show that where as the latter becomes overconservative when there is considerable confounding due to PS (i.e. when , is large), DC performs well for all values of ,. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Protein C and protein S levels can be accurately determined within 24 hours of diagnosis of acute venous thromboembolismINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 1 2006M. J. KOVACS Summary In the 50% of cases of acute idiopathic venous thromboembolism, laboratory testing for inherited causes is often performed. Most physicians are under the impression that assays for protein C and protein S should not be measured at the time of diagnosis because of a high false positive rate. We performed a prospective cohort study from two outpatient thromboembolism clinics on consecutive patients with an objectively confirmed diagnosis of first acute idiopathic venous thromboembolism. Assays for protein C and protein S were performed prior to the initiation of oral anticoagulation therapy and within 24 h of diagnosis of venous thromboembolism. Abnormal results were repeated when patients discontinued oral anticoagulant therapy. Of 253 patients tested for both protein C and protein S, 229 (91%; 95% confidence interval 87,94%) were negative and 484 of 508 (95%) tests were normal. Of the 24 initial abnormal results, 21 were repeated and 10 (48%; 95% confidence interval 26,70%) were still abnormal. Overall, 97.8% of initial protein C and protein S results were accurate. If protein C and protein S are measured at the time of diagnosis of acute venous thromboembolism, the majority of the results will be normal and false positives are uncommon. [source] Why do primary care doctors diagnose depression when diagnostic criteria are not met?INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH, Issue 3 2000Michael Höfler Abstract This study examines predictors of false positive depression diagnoses by primary care doctors in a sample of primary care attendees, taking the patients' diagnostic status from a self-report measure (Depression Screening Questionnaire, DSQ) as a yardstick against which to measure doctors' correct and false positive recognition rates. In a nationwide study, primary care patients aged 15,99 in 633 doctors' offices completed a self-report packet that included the DSQ, a questionnaire that assesses depression symptoms on a three-point scale to provide diagnoses of depression according to the criteria of DSM-IV and ICD-10. Doctors completed an evaluation form for each patient seen, reporting the patient's depression status, clinical severity, and treatment choices. Predictor analyses are based on 16,909 patient-doctor records. Covariates examined included depression symptoms, the total DSQ score, number and persistence of depression items endorsed, patient's prior treatment, history of depression, age and gender. According to the DSQ, 11.3% of patients received a diagnosis of ICD-10 depression, 58.9% of which were correctly identified by the doctor as definite threshold, and 26.2% as definite subthreshold cases. However, an additional 11.7% of patients not meeting the minimum DSQ threshold were rated by their doctors as definitely having depression (the false positive rate). Specific DSQ depression items endorsed, a higher DSQ total score, more two-week depression symptoms endorsed, female gender, higher age, and patient's prior treatment were all associated with an elevated rate of false positive diagnoses. The probability of false positive diagnoses was shown to be affected more by doctors ignoring the ,duration of symptoms' criterion than by doctors not following the ,number of symptoms' criterion for an ICD or DSM diagnosis of depression. A model selection procedure revealed that it is sufficient to regress the ,false positive diagnoses' on the DSQ-total score, symptoms of depressed mood, loss of interest, and suicidal ideation; higher age; and patient's prior treatment. Further, the total DSQ score was less important in prediction if there was a prior treatment. The predictive value of this model was quite good, with area under the ROC-curve = 0.86. When primary care doctors use depression screening instruments they are oversensitive to the diagnosis of depression. This is due to not strictly obeying the two weeks duration required by the diagnostic criteria of ICD-10 and DSM-IV. False positive rates are further increased in particular by the doctor's knowledge of a patient's prior treatment history as well as the presence of a few specific depression symptoms. Copyright © 2000 Whurr Publishers Ltd. [source] Improved prenatal aneuploidy screening using the novel advanced first-trimester screening algorithm: A multicenter study of 10,017 pregnanciesJOURNAL OF CLINICAL ULTRASOUND, Issue 7 2008Peter Schmidt MD Abstract Purpose. It has been postulated that the maternal age component should be completely excluded from first-trimester screening (FTS) for fetal aneuploidies. In this study, we tested a new algorithm known as advanced first-trimester screening (AFS), which disregards maternal age. Method. In a multicenter study, FTS findings were retrieved from 10,017 pregnancies. FTS risk assessment was performed using the Nicolaides method, and the AFS score was calculated. The results of both methods were compared. Results. Within this population, 81 fetuses had an abnormal karyotype. The sensitivity of the 2 algorithms was 86.4%. When the AFS method was used, the positive predictive value rose from 9.6% (FTS) to 12.4% (AFS). Using AFS, the test positive rate could be decreased by 161 cases (,22.2%) (p < 0.0001), due to a reduction of false positive cases. As a result, the false positive rate of AFS was 24.5% lower than that of FTS, while the same number of aneuploidies was detected. Conclusion. AFS can markedly reduce the rate of false positive test results. If these results are confirmed by larger multicenter studies, the new AFS will represent a great improvement in fetal aneuploidy screening. © 2008 Wiley Periodicals, Inc. J Clin Ultrasound, 2008 [source] Assessment of obesity in children and adolescents: synthesis of recent systematic reviews and clinical guidelinesJOURNAL OF HUMAN NUTRITION & DIETETICS, Issue 3 2010J. J. Reilly Abstract This review summarises recent systematic reviews and evidence-based guidelines that deal with the issue of how best to diagnose or define obesity in children and adolescents. A recent systematic review showed that parents typically fail to recognise obesity in their children and adolescents, and a good deal of other evidence suggests that health professionals under-diagnose obesity in children and adolescents when using informal methods based on observation. There is therefore a need for practical, objective, methods that both identify the fattest children and adolescents adequately, and identify those who are at greatest risk of the ,co-morbidities' of obesity. A large body of consistent evidence shows that a high body mass index (BMI) for age and sex identifies the fattest children adequately, with low,moderate false negative rate and a low false positive rate. Furthermore, children and adolescents at high BMI for age are at much greater risk of the co-morbidities of obesity. A recent systematic review found that the use of BMI for age with national reference data and cut-off points (such as the 95th percentile to define obesity) was superior to the Cole,International Obesity Task Force international approach for defining obesity based on BMI for age. The same systematic review also found no evidence that use of waist circumference for age improved the diagnosis of obesity, or the cardio-metabolic co-morbidities of obesity, in children and adolescents. Recent systematic reviews are therefore supportive of current guidelines that recommend percentile-based cut-offs relative to national reference data to (e.g. BMI at or above the 95th or 98th percentile in the UK) to define obesity for clinical applications in children and adolescents. [source] A further investigation on a MALDI-based method for evaluation of markers of renal damageJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 12 2009Annunziata Lapolla Abstract The validity of the urinary protein profile to characterize the pathological states of diabetic, nephropathic and diabetic,nephropathic patients was considered on the basis of previously obtained results by MALDI/MS, showing a different abundance ratio of the collagen ,1 and ,5 chain precursor fragments at m/z 1219 and 2049 and of the uromodulin precursor fragment at m/z 1912 observed in healthy subjects and patients; a larger number of subjects was examined and the obtained results were statistically evaluated. The p values related to the observed differences indicate that they are statistically significant when comparing all patients versus healthy controls, diabetic with normo or microalbuminuria versus nephropathic with advanced renal disease patients and diabetic with normo or microalbuminuria versus diabetic with advanced nephropathy patients. The scatter plot matrix gives evidence of the strict inverse relationship between the abundances of ions at m/z 1912 and 1219, the correlation coefficient being particularly high (r = 0.921, p < 0.001). The relationship between the true positive rate (sensitivity) and false positive rate (1,specificity) for every possible cutoff value in abundance of the considered ionic species was investigated through the receiver-operating characteristic (ROC) curve. The obtained data indicate that a good differentiation of nephropathic patients with advanced renal disease and diabetic patients with advanced nephropathy versus healthy subjects can be easily obtained by this approach. Copyright © 2009 John Wiley & Sons, Ltd. [source] Efficient recognition of protein fold at low sequence identity by conservative application of Psi-BLAST: validation,JOURNAL OF MOLECULAR RECOGNITION, Issue 2 2005F. J. Stevens Abstract A substantial fraction of protein sequences derived from genomic analyses is currently classified as representing ,hypothetical proteins of unknown function'. In part, this reflects the limitations of methods for comparison of sequences with very low identity. We evaluated the effectiveness of a Psi-BLAST search strategy to identify proteins of similar fold at low sequence identity. Psi-BLAST searches for structurally characterized low-sequence-identity matches were carried out on a set of over 300 proteins of known structure. Searches were conducted in NCBI's non-redundant database and were limited to three rounds. Some 614 potential homologs with 25% or lower sequence identity to 166 members of the search set were obtained. Disregarding the expect value, level of sequence identity and span of alignment, correspondence of fold between the target and potential homolog was found in more than 95% of the Psi-BLAST matches. Restrictions on expect value or span of alignment improved the false positive rate at the expense of eliminating many true homologs. Approximately three-quarters of the putative homologs obtained by three rounds of Psi-BLAST revealed no significant sequence similarity to the target protein upon direct sequence comparison by BLAST, and therefore could not be found by a conventional search. Although three rounds of Psi-BLAST identified many more homologs than a standard BLAST search, most homologs were undetected. It appears that more than 80% of all homologs to a target protein may be characterized by a lack of significant sequence similarity. We suggest that conservative use of Psi-BLAST has the potential to propose experimentally testable functions for the majority of proteins currently annotated as ,hypothetical proteins of unknown function';. Copyright © 2004 John Wiley & Sons, Ltd. [source] Detection of Right-to-Left Shunts: Comparison between the International Consensus and Spencer Logarithmic Scale CriteriaJOURNAL OF NEUROIMAGING, Issue 4 2008Annabelle Y. Lao ABSTRACT BACKGROUND International Consensus Criteria (ICC) consider right-to-left shunt (RLS) present when Transcranial Doppler (TCD) detects even one microbubble (,B). Spencer Logarithmic Scale (SLS) offers more grades of RLS with detection of >30 ,B corresponding to a large shunt. We compared the yield of ICC and SLS in detection and quantification of a large RLS. SUBJECTS AND METHODS We prospectively evaluated paradoxical embolism in consecutive patients with ischemic strokes or transient ischemic attack (TIA) using injections of 9 cc saline agitated with 1 cc of air. Results were classified according to ICC [negative (no ,B), grade I (1-20 ,B), grade II (>20 ,B or "shower" appearance of ,B), and grade III ("curtain" appearance of ,B)] and SLS criteria [negative (no ,B), grade I (1-10 ,B), grade II (11-30 ,B), grade III (31100 ,B), grade IV (101300 ,B), grade V (>300 ,B)]. The RLS size was defined as large (>4 mm) using diameter measurement of the septal defects on transesophageal echocardiography (TEE). RESULTS TCD comparison to TEE showed 24 true positive, 48 true negative, 4 false positive, and 2 false negative cases (sensitivity 92.3%, specificity 92.3%, positive predictive value (PPV) 85.7%, negative predictive value (NPV) 96%, and accuracy 92.3%) for any RLS presence. Both ICC and SLS were 100% sensitive for detection of large RLS. ICC and SLS criteria yielded a false positive rate of 24.4% and 7.7%, respectively when compared to TEE. CONCLUSIONS Although both grading scales provide agreement as to any shunt presence, using the Spencer Scale grade III or higher can decrease by one-half the number of false positive TCD diagnoses to predict large RLS on TEE. [source] Genome-wide association studies and the genetic dissection of complex traits,AMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2009Paola Sebastiani The availability of affordable high throughput technology for parallel genotyping has opened the field of genetics to genome-wide association studies (GWAS), and in the last few years hundreds of articles reporting results of GWAS for a variety of heritable traits have been published. What do these results tell us? Although GWAS have discovered a few hundred reproducible associations, this number is underwhelming in relation to the huge amount of data produced, and challenges the conjecture that common variants may be the genetic causes of common diseases. We argue that the massive amount of genetic data that result from these studies remains largely unexplored and unexploited because of the challenge of mining and modeling enormous data sets, the difficulty of using nontraditional computational techniques and the focus of accepted statistical analyses on controlling the false positive rate rather than limiting the false negative rate. In this article, we will review the common approach to analysis of GWAS data and then discuss options to learn more from these data. We will use examples from our ongoing studies of sickle cell anemia and also GWAS in multigenic traits. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] The association between preeclampsia and placental disruption induced by chorionic villous samplingPRENATAL DIAGNOSIS, Issue 6 2010Antonio Farina Abstract Objectives The objectives of this study were (1) to evaluate if the elevation of maternal serum ,-feto protein (MSAFP) and pregnancy-associated placental protein-A (PAPP-A) in the maternal blood after chorionic villous sampling (CVS) is associated with a higher preeclampsia (PE) rate and (2) to verify the clinical utility of the analytes elevation for predicting PE. Methods A prospective study on 106 subjects who underwent CVS was performed. At the time of CVS, two blood samples were obtained for MSAFP and PAPP-A dosage, the first just before the procedure, and the second one 30 min after the procedure. Cases with abnormal karyotype, major anomalies or preterm delivery were subsequently excluded. The ratio between the two samples was calculated as , (MSAFP or PAPP-A post-CVS/MSAFP or PAPP-A pre-CVS) and it was related to subsequent occurrence of PE. Results The rate of PE was 5.7% (6/106). Both MSAFP and PAPP-A levels were higher after than before CVS (median ratio = 8.33 and 1.08, respectively). Cases developing PE had significantly higher MSAFP ratio (11.6 vs 7.4, p -value = 0.04) and PAPP-A ratio (1.13 vs 1.08, p -value = 0.009) than those who did not develop PE. Receiver operating characteristic curve analysis showed that PAPP-A ratio was a better predictor of subsequent PE than MSAFP ratio: at a fixed false positive rate of 10%, the detection rates for MSAFP and PAPP-A ratios were 33 and 50%, respectively. Conclusion The elevation of MSAFP and PAPP-A observed with CVS is associated with increased risk of subsequent PE. The ability of such increases to predict PE appears to be modest. Copyright © 2010 John Wiley & Sons, Ltd. [source] Early onset preeclampsia and second trimester serum markersPRENATAL DIAGNOSIS, Issue 12 2009Geralyn M. Lambert-Messerlian Abstract Objective To examine serum markers measured in the second trimester to identify women who subsequently develop preeclampsia. Methods Clinically defined preeclampsia was confirmed in 45 women who had provided a serum sample as part of Down syndrome screening. Preeclampsia was categorized as mild or severe, as well as early (<32 weeks) or late onset. Each case was matched with five controls based on gestational age and date of serum collection. Stored sera were retrieved and tested for inhibin A, soluble vascular endothelial growth factor receptor 1 (sVEGF R1), placental growth factor (PlGF), and endoglin. Results were converted to multiples of the median (MoM) and compared in case and control pregnancies. Univariate analysis was used to identify the strongest markers, which were then used in a multivariate model. Results Inhibin A, PlGF, and endoglin were consistently associated with preeclampsia, especially for early onset disease. A multivariate model using the three markers could identify 50% of the pregnancies with early onset preeclampsia with a 2% false positive rate. Conclusion The levels of inhibin A, PlGF, and endoglin in the second trimester can be combined using a predictive model to provide individualized risk estimates for early onset preeclampsia. Copyright © 2009 John Wiley & Sons, Ltd. [source] The proform of eosinophil major basic protein: a new maternal serum marker for adverse pregnancy outcomePRENATAL DIAGNOSIS, Issue 11 2009Kasper Pihl Abstract Objective To establish the first trimester serum levels of the proform of eosinophil major basic protein (proMBP) in pregnancies with adverse outcome. Furthermore, to determine the screening performance using proMBP alone and in combination with other first trimester markers. Methods A case-control study was conducted in a primary hospital setting. The proMBP concentration was measured in cases with small-for-gestational age (SGA) (n = 150), spontaneous preterm delivery (n = 88), preeclampsia (n = 40), gestational hypertension (n = 10) and in controls (n = 500). Concentrations were converted to multiples of the median (MoM) in controls and groups were compared using Mann,Whitney U -test. Logistic regression analysis was used to determine significant factors for predicting adverse pregnancy outcome. Screening performance was assessed using receiver operating characteristic curves. Results The proMBP median was significantly reduced in pregnancies with SGA (0.81 MoM), spontaneous preterm delivery (0.83 MoM), preeclampsia (0.88 MoM) and gestational hypertension (0.60 MoM). The best screening performance was found for preeclampsia including the covariates proMBP and nulliparity yielding an area under the curve equal to 0.737 (p < 0.0005) and a 75% detection rate for a 30% false positive rate. Conclusion The proMBP is a novel first trimester serum marker for adverse pregnancy outcome. Copyright © 2009 John Wiley & Sons, Ltd. [source] Cost-effectiveness of prenatal screening for thalassaemia in Hong KongPRENATAL DIAGNOSIS, Issue 11 2004K. Y. Leung Abstract Objectives To determine the cost effectiveness of a universal prenatal screening program for ,- and ,-thalassaemia. Methods We retrospectively reviewed our program from 1998 to 2002, and calculated the direct and indirect costs of various components. Results 18 936 women were screened at our prenatal clinic and 153 couples were subsequently referred to our Prenatal Diagnostic Centre for counselling and further investigations. In addition, there were 238 tertiary referrals and 157 self-referrals. After investigations, 84 fetuses were at risk of ,-thalassaemia major/,-E thalassaemia, 19 of them were affected and 18 were aborted. The total expenditure on our program (HK$10.0 million) would be less than the postnatal service costs (HK$40.4 million) for 18,-thalassaemia major fetuses if they were born. Of 361 women at risk of carrying a homozygous ,0 -thalassaemia fetus, 311 (86.2%) opted for the indirect approach (using serial ultrasound examinations to exclude Hb Bart's disease), and 76 (24.5%) subsequently underwent an invasive test for a definitive diagnosis. The sensitivity and false positive rate of this indirect approach was 100.0% and 2.9% respectively. Conclusion It is cost effective to run a universal prenatal screening program in an area where both ,-thalassaemia and ,-thalassaemia are prevalent. The indirect approach can effectively avoid an invasive test in unaffected pregnancies. Copyright © 2004 John Wiley & Sons, Ltd. [source] Detection of maternal serum hCG glycoform variants in the second trimester of pregnancies affected by Down syndrome using a lectin immunoassayPRENATAL DIAGNOSIS, Issue 1 2003J. A. Talbot Abstract Aim To assess whether glycoform variants of human chorionic gonadotrophin (hCG) are present in altered concentrations in the maternal serum in pregnancies affected by Down syndrome. Methods In a series of 50 cases of pregnancies complicated by Down syndrome and 278 unaffected pregnancies, we have examined maternal serum levels of hCG glycoforms (GlyhCG) in samples collected in the second trimester (14 to 21 weeks) using a sialic acid binding lectin immunoassay. We have compared these levels with those of other second trimester serum markers (Free ,-hCG, alpha fetaprotein (AFP) and Total hCG) and modelled detection rates and false positive rates of various biochemical markers in conjunction with maternal age using a maternal age standardized population. Results Maternal serum GlyhCG in cases of Down syndrome was significantly elevated (Median MoM 1.81) with 15 of 50 (30%) cases above the 95th centile for unaffected pregnancies. Free ,-hCG was also elevated (Median MoM 2.16) with 18 of 50 (36%) cases above the 95th centile. AFP levels were reduced (Median MoM 0.75) with 9 of 50 (18%) cases below the 5th centile. Total hCG levels whilst elevated (Median MoM 1.88) had only 15 of 50 (30%) cases above the 95th centile. Maternal serum GlyhCG levels showed significant correlation with total hCG and free ,-hCG (r = 0.6880 and 0.6922) in the Down group but not with AFP (r = 0.1237). When GlyhCG was combined together with AFP and maternal age, at a 5% false positive rate, the modelled detection rate was 53%, some 13% lower than when free ,-hCG was used and some 7% lower than when total hCG was used. Conclusion Maternal serum GlyhCG, as measured by the sialic acid,binding lectin immunoassay is unlikely to be of additional value when screening for Down syndrome in the second trimester. Copyright © 2002 John Wiley & Sons, Ltd. [source] Serially coupled microcolumn reversed phase liquid chromatography for shotgun proteomic analysisPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 7 2009Dingyin Tao Abstract Microcolumn RPLC (,RPLC) is one of the optimum separation modes for shotgun proteomic analysis. To identify as many proteins as possible by MS/MS, the improvement on separation efficiency and peak capacity of ,RPLC is indispensable. Although the increase in column length is one of the effective solutions, the preparation of a long microcolumn is rather difficult due to the high backpressure generated during the packing procedure. In our recent work, through connecting microcolumns of 5, 10, and 15,cm length via unions with minimal dead volume, long microcolumns with length up to 30,cm were obtained, with which 318 proteins were identified from proteins extracted from Escherichia coli by ,RPLC-ESI MS/MS, and similar distributions of Mw and pI were found with single and various coupled microcolumns. Furthermore, by using MS/MS with improved sensitivity, with such a serially coupled 30,cm long microcolumn, 1692 proteins were identified within 7,h from rat brain tissue, with false positive rate (FPR) <1%. All these results demonstrated that serially couple microcolumns might be of great promising to improve the separation capacity of ,RPLC in shotgun proteomic analysis. [source] Identification of secreted proteins regulated by cAMP in glioblastoma cells using glycopeptide capture and label-free quantificationPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2009Jennifer J. Hill Dr. Abstract Exposure of glioblastoma U87MG cells to a cAMP analog leads to a decrease in proliferation, invasion, and angiogenic potential. Here, we apply a label-free MS-based approach to identify formerly N -linked glycopeptides that change in abundance upon cAMP treatment. Over 150 unique glycopeptides in three biological repetitions were quantified, leading to the identification of 14 upregulated proteins and 21 downregulated proteins due to cAMP treatment. Of these, eight have been validated, either through comparison with microarray data or by Western blot. We estimate our ability to identify differentially expressed peptides at greater than 85% in a single biological repetition, while the analysis of multiple biological repetitions lowers the false positive rate to ,2%. Many of the proteins identified in this study are involved in cell signaling and some, such as Tenascin C, Cathepsin L, Neuroblastoma suppressor of tumorigenicity, and AXL/UFO tyrosine,protein kinase receptor, have been previously shown to be involved in glioblastoma progression. We also identify several semitryptic peptides that increase in abundance upon cAMP treatment, suggesting that cAMP regulates protease activity in these cells. Overall, these results demonstrate the benefits of using a highly specific enrichment method for quantitative proteomic experiments. [source] A new strategy to filter out false positive identifications of peptides in SEQUEST database search resultsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 22 2007Jiyang Zhang Abstract Based on the randomized database method and a linear discriminant function (LDF) model, a new strategy to filter out false positive matches in SEQUEST database search results is proposed. Given an experiment MS/MS dataset and a protein sequence database, a randomized database is constructed and merged with the original database. Then, all MS/MS spectra are searched against the combined database. For each expected false positive rate (FPR), LDFs are constructed for different charge states and used to filter out the false positive matches from the normal database. In order to investigate the error of FPR estimation, the new strategy was applied to a reference dataset. As a result, the estimated FPR was very close to the actual FPR. While applied to a human K562 cell line dataset, which is a complicated dataset from real sample, more matches could be confirmed than the traditional cutoff-based methods at the same estimated FPR. Also, though most of the results confirmed by the LDF model were consistent with those of PeptideProphet, the LDF model could still provide complementary information. These results indicate that the new method can reliably control the FPR of peptide identifications and is more sensitive than traditional cutoff-based methods. [source] Improved detection of reactive metabolites with a bromine-containing glutathione analog using mass defect and isotope pattern matchingRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 9 2010André LeBlanc Drug bioactivation leading to the formation of reactive species capable of covalent binding to proteins represents an important cause of drug-induced toxicity. Reactive metabolite detection using invitro microsomal incubations is a crucial step in assessing potential toxicity of pharmaceutical compounds. The most common method for screening the formation of these unstable, electrophilic species is by trapping them with glutathione (GSH) followed by liquid chromatography/mass spectrometry (LC/MS) analysis. The present work describes the use of a brominated analog of glutathione, N -(2-bromocarbobenzyloxy)-GSH (GSH-Br), for the invitro screening of reactive metabolites by LC/MS. This novel trapping agent was tested with four drug compounds known to form reactive metabolites, acetaminophen, fipexide, trimethoprim and clozapine. Invitro rat microsomal incubations were performed with GSH and GSH-Br for each drug with subsequent analysis by liquid chromatography/high-resolution mass spectrometry on an electrospray time-of-flight (ESI-TOF) instrument. A generic LC/MS method was used for data acquisition, followed by drug-specific processing of accurate mass data based on mass defect filtering and isotope pattern matching. GSH and GSH-Br incubations were compared to control samples using differential analysis (Mass Profiler) software to identify adducts formed via the formation of reactive metabolites. In all four cases, GSH-Br yielded improved results, with a decreased false positive rate, increased sensitivity and new adducts being identified in contrast to GSH alone. The combination of using this novel trapping agent with powerful processing routines for filtering accurate mass data and differential analysis represents a very reliable method for the identification of reactive metabolites formed in microsomal incubations. Copyright © 2010 John Wiley & Sons, Ltd. [source] The combined effect of SNP-marker and phenotype attributes in genome-wide association studiesANIMAL GENETICS, Issue 2 2009E. K. F. Chan Summary The last decade has seen rapid improvements in high-throughput single nucleotide polymorphism (SNP) genotyping technologies that have consequently made genome-wide association studies (GWAS) possible. With tens to hundreds of thousands of SNP markers being tested simultaneously in GWAS, it is imperative to appropriately pre-process, or filter out, those SNPs that may lead to false associations. This paper explores the relationships between various SNP genotype and phenotype attributes and their effects on false associations. We show that (i) uniformly distributed ordinal data as well as binary data are more easily influenced, though not necessarily negatively, by differences in various SNP attributes compared with normally distributed data; (ii) filtering SNPs on minor allele frequency (MAF) and extent of Hardy,Weinberg equilibrium (HWE) deviation has little effect on the overall false positive rate; (iii) in some cases, filtering on MAF only serves to exclude SNPs from the analysis without reduction of the overall proportion of false associations; and (iv) HWE, MAF and heterozygosity are all dependent on minor genotype frequency, a newly proposed measure for genotype integrity. [source] Impact and Quantification of the Sources of Error in DNA Pooling DesignsANNALS OF HUMAN GENETICS, Issue 1 2009A. Jawaid Summary The analysis of genome wide variation offers the possibility of unravelling the genes involved in the pathogenesis of disease. Genome wide association studies are also particularly useful for identifying and validating targets for therapeutic intervention as well as for detecting markers for drug efficacy and side effects. The cost of such large-scale genetic association studies may be reduced substantially by the analysis of pooled DNA from multiple individuals. However, experimental errors inherent in pooling studies lead to a potential increase in the false positive rate and a loss in power compared to individual genotyping. Here we quantify various sources of experimental error using empirical data from typical pooling experiments and corresponding individual genotyping counts using two statistical methods. We provide analytical formulas for calculating these different errors in the absence of complete information, such as replicate pool formation, and for adjusting for the errors in the statistical analysis. We demonstrate that DNA pooling has the potential of estimating allele frequencies accurately, and adjusting the pooled allele frequency estimates for differential allelic amplification considerably improves accuracy. Estimates of the components of error show that differential allelic amplification is the most important contributor to the error variance in absolute allele frequency estimation, followed by allele frequency measurement and pool formation errors. Our results emphasise the importance of minimising experimental errors and obtaining correct error estimates in genetic association studies. [source] Ignoring Distant Genealogic Loops Leads to False-positives in Homozygosity MappingANNALS OF HUMAN GENETICS, Issue 6 2006F. Liu Summary Distant consanguineous loops are often unknown or ignored during homozygosity mapping analysis. This may potentially lead to an increased rate of false-positive linkage results. We show that failure to take into account the distant loops may seriously underestimate the degree of consanguinity, especially for people from genetically isolated populations; in 6 Alzheimer's disease (AD) patients the distant loops accounted for 57.7 % of inbreeding on average. Theoretical evaluation showed that ignoring distant loops, which account for 18-75% of inbreeding, inflates the frequency of false positive conclusions substantially in 2-point linkage analysis, up to several hundred times. In multipoint linkage analysis of the 6 AD patients a chromosome-wide "empirical" significance of 5% corresponded to a true false positive rate of 11.1%. We show that converting multiple loops to a hypothetical loop capturing all inbreeding may be a convenient solution to avoid false positive results. When extended genealogic data are not available a hypothetical loop may still be constructed based on genomic data. [source] Development of a parathyroid database in Melbourne and review of the last 50 casesANZ JOURNAL OF SURGERY, Issue 9 2004Meei J. Yeung Background: Minimally invasive parathyroidectomy (MIP) is only possible if preoperative localization studies accurately identify the abnormal parathyroid tissue. The aim of the present paper was to evaluate the accuracy of these studies in our geographical region and the consequences on MIP. Methods: A Filemaker Pro database was designed and a retrospective analysis was carried out on the last 50 parathyroidectomies. Results: There were a total of 49 patients who underwent parathyroidectomy; with one patient having two operations. Forty-nine preoperative ultrasound localization studies were performed. Ultrasound sensitivity of correct localization of abnormal parathyroids was 41% with a false positive rate of 25%. Twenty-two sestamibi scans identified 14 abnormal parathyroids. Sestamibi scanning had a sensitivity of 32% for correct localization and a false positive rate of 32%. There were 16 different radiologists or nuclear medicine physicians involved with the nuclear medicine scans, and 22 different radiologists involved in the preoperative ultrasound scans. Forty-seven patients were cured of hyperparathyroidism after a primary operation, with a total of 48 patients in all being cured following re-exploration. One patient was lost to follow up. The success of primary exploration was therefore 96% and following re-exploration this increased to 98%. Conclusion: We found preoperative localization studies to have low sensitivities and high false positive rates. To move successfully towards MIP, we need to identify a radiologist with a special interest in localization studies to achieve greater accuracy. [source] Bayesian Methods for Predicting Interacting Protein Pairs Using Domain InformationBIOMETRICS, Issue 3 2007Inyoung Kim Summary Protein,protein interactions (PPIs) play important roles in most fundamental cellular processes including cell cycle, metabolism, and cell proliferation. Therefore, the development of effective statistical approaches to predicting protein interactions based on recently available large-scale experimental data is very important. Because protein domains are the functional units of proteins and PPIs are mostly achieved through domain,domain interactions (DDIs), the modeling and analysis of protein interactions at the domain level may be more informative and insightful. However, due to the large number of domains, the number of parameters to be estimated is very large, yet the amount of information for statistical inference is quite limited. In this article we propose a full Bayesian method and a semi-Bayesian method for simultaneously estimating DDI probabilities, the false positive rate, and the false negative rate of high-throughput data through integrating data from several organisms. We also propose a model to associate protein interaction probabilities with domain interaction probabilities that reflects the number of domains in each protein. Our Bayesian methods are compared with the likelihood-based approach (Deng et al., 2002, Genome Research12, 1504,1508; Liu, Liu, and Zhao, 2005, Bioinformatics21, 3279,3285) developed using the expectation maximization algorithm. We show that the full Bayesian method has the smallest mean square error through both simulations and theoretical justification under a special scenario. The large-scale PPI data obtained from high-throughput yeast two-hybrid experiments are used to demonstrate the advantages of the Bayesian approaches. [source] | |||||||||||||||||||||||||