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Ikenberg H.,Cytomol | Bergeron C.,Laboratoire Cerba | Schmidt D.,Institute for Pathology | Griesser H.,Cytodiagnostics | And 13 more authors.
Journal of the National Cancer Institute | Year: 2013

Background: Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing. Methods: A total of 27349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined. Results: The p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P <. 001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P =. 15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P =. 03) but less specific (93.0% vs 96.2%; P <. 001). Conclusions: The p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations. © The Author 2013. Published by Oxford University Press.

Denton K.J.,North Bristol NHS Trust | Bergeron C.,Laboratoire Cerba | Klement P.,MTM Laboratories | Trunk M.J.,MTM Laboratories | And 3 more authors.
American Journal of Clinical Pathology | Year: 2010

We analyzed the performance of p16INK4a immunocytochemistry on a series of 810 retrospectively collected atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cases with available biopsy follow-up data, including 94 cases of cervical intraepithelial neoplasia (CIN) 2 and 128 cases of CIN 3. Human papillomavirus (HPV) testing was performed from the same residual liquid-based cytologic specimen, and results for both tests were correlated with histologic follow-up data. Sensitivity values for high-grade CIN (HGCIN) confirmed on biopsy within 6 months were 92.6% (ASC-US) and 92.2% (LSIL) for cytotechnologists' reviews of p16 cytology and 90.1% (ASC-US) and 95.7% (LSIL) for HPV testing. Sensitivity rates of initial pathologists' reviews were slightly lower, 76.4% to 80.1%, with levels comparable to cytotechnologists' results after adjudication. The specificity of p16 cytology for HGCIN detection was significantly higher than for HPV testing for cytotechnologists and pathologists: 63.2% to 71.1% (p16 cytology) vs 37.8% for HPV in ASC-US (P < .001) and 37.3% to 53.3% (p16 cytology) vs 18.5% for HPV in LSIL (P < .001). This evaluation of the diagnostic performance of p16 cytology confirms the potential of this stain for the efficient triage of ASC-US and LSIL cytologic results. © American Society for Clinical Pathology.

Zegers I.,European Commission | Beetham R.,Frenchay Hospital | Keller T.,Acomed Statistik | Sheldon J.,St Georges Hospital | And 5 more authors.
Clinical Chemistry | Year: 2013

BACKGROUND: Different methods for ceruloplasmin tend to give different results in external quality assessment schemes. During the production of the certified reference material ERM-DA470k/IFCC discrepant measurement results were also found for ceruloplasmin measured with different methods, and consequently the protein could not be certified in the material. METHODS: We performed a commutability study with 30 serum samples and the reference materials ERMDA470, ERM-DA470k/IFCC, and ERM-DA472/ IFCC, using 6 different methods. Data were analyzed according to the CLSI Guideline C53-A to assess whether the reference materials had the same behavior as the serum samples with respect to measurement results obtained with combinations of the methods used. RESULTS: Measurement results from different methods showed a good linear correlation for the serum samples. ERM-DA470 showed marked noncommutability for certain combinations of methods. ERMDA470k/ IFCC and ERM-DA472/IFCC were commutable for more combinations of methods. The lack of commutability of ERM-DA470 for certain combinations of methods correlates with results from the UK National External Quality Assessment Service showing discrepancies between results from these methods. For serum stored in the presence of sodium azide the results from different methods are essentially equivalent. CONCLUSIONS: Ceruloplasmin in ERM-DA470 is a fully documented example of a situation in which, due to lack of commutability, the use of a common material for calibration did not lead to harmonization. © 2013 American Association for Clinical Chemistry.

Bergeron C.,Laboratoire Cerba | Ordi J.,Clinic Hospital Universitari | Schmidt D.,Institute of Pathology | Trunk M.J.,MTM Laboratories | And 3 more authors.
American Journal of Clinical Pathology | Year: 2010

The histopathologic interpretation of cervical intraepithelial neoplasia (CIN) is subject to a high level of interobserver variability and a substantial number of false-positive and false-negative results. We assessed the impact of the conjunctive interpretation of p16INK4a-immunostained slides on the accuracy of community-based pathologists in diagnosing high-grade cervical intraepithelial neoplasia (CIN; CIN 2 and CIN 3) in biopsy specimens. Twelve pathologists rendered independent diagnoses on a set of 500 H&E-stained cervical punch and conization specimens. Results were compared with a dichotomized "gold standard" established by consensus of 3 gynecopathology experts. When p16INK4a-immunostained slides were added and conjunctively interpreted with the H&E-stained slides, a significant increase in diagnostic accuracy for the detection of high-grade CIN was observed (P = .0004). Sensitivity for high-grade CIN was increased by 13%, cutting the rate of false-negative results in half. Agreement of community-based pathologists in diagnosing high-grade CIN was significantly improved (mean κ values advanced from 0.566 to 0.749; P < .0001). Reproducibility of p16INK4a stain interpretation was excellent ( κ = 0.899). Our results show that conjunctive interpretation of p16INK4a-stained slides could significantly improve the routine interpretation of cervical histopathology. © American Society for Clinical Pathology.

Haeckel R.,Bremer Zentrum For Laboratoriumsmedizin | Gurr E.,Abteilung Klinische Chemie | Keller T.,ACOMED statistik
LaboratoriumsMedizin | Year: 2016

Many laboratories observe that requirements of the Guideline of the German Medical Association RiliBÄK for the internal quality assurance are difficult to fulfill in the lower part of the measurement interval (e.g. thrombocyte count at 50·109/L). With 10 measurands, the RiliBÄK contain special limits for lower measurement quantities. But, these limits lead to artificial "jumps" and even may be too stringent in the very low region of the measurement interval. Requirements which are too stringent usually lead to repeats and unnecessary costs, and to unnecessary time delay. The DGKL working group Guide Limits proposes variable permissible limits depending on the measurand concentration applied in the control material. Then, in the 10 critical cases, higher permissible limits are obtained in the very low part of measurement intervals. The control materials used in ring trials should contain concentrations close to the lower decision limits. Then, the permissible limits provided by the RiliBÄK also appear too stringent in the lower part of the measurement intervals of many measurands. © 2016 Walter de Gruyter GmbH, Berlin/Boston.

Keller T.,ACOMED Statistik | Brinkmann T.,Labor Lademannbogen MVZ GmbH
Clinical Laboratory | Year: 2014

Background: Carryover experiments are widely used for clinical chemistry and immunochemistry analysers to evaluate and validate carryover effects. The experimental design is well described. However, there is no guideline on the statistical approach on data analysis, especially if absence of carryover has to be shown. The only reporting of carryover in ppm is not helpful because its uncertainty is not taken into account. Furthermore, the most commonly used method fails to demonstrate the absence of carryover. We propose a step-by-step guidance applying a new statistical design for analysis of carryover studies based on equivalence testing, and provide a sample based tutorial. Methods: For statistical analysis of carryover effects an one-sided version of equivalence testing by comparing the difference with a predefined limit (i.e., a test of non-superiority) is used. The methodology is demonstrated by measuring total βhCG in human serum samples with a UniCel DxI 880 analyser. Results: A new statistical approach based on equivalence testing has been developed for analysis of data resulting from a typical experimental protocol for carryover studies. Experiments using 8 (11) cycles of high and low concentration samples are appropriate to validate the absence of carryover with 80% (90%) power and an α-level of 0,05 if no carryover is expected. We propose to predefine an acceptance criterion based on the imprecision (here: expressed as one standard deviation) observed for those replicates of the low concentration samples expected to be unaffected by carryover. In the demonstration, the absence of carry-over was concluded with a significance of p < 0.05. Conclusions: Appropriate statistical methods should be applied when the target of a method-validation experiment is (i) absence of any effect, (ii) non-inferiority / non-superiority or (iii) equivalence. Using the example of carryover studies, we show that one-sided equivalence testing is the proper model, and propose a guidance for analysis of these experiments. The example of carryover illustrates a methodology which is also applicable for analysis of a wide range of experimental approaches, including method comparison, commutability and robustness.

Fillee C.,Cliniques Universitaires St Luc | Keller T.,Acomed Statistik | Mourad M.,Cliniques Universitaires St Luc | Brinkmann T.,Ruhr University Bochum | Ketelslegers J.-M.,Cliniques Universitaires St Luc
Clinical Endocrinology | Year: 2012

Background, objective An international consensus conference underlined the importance of defining upper parathyroid hormone (PTH) reference values based on 25-OH-vitamin D [25(OH)D] to diagnose mild primary hyperparathyroidism. We determined the importance of this factor in a Belgian population. Design, patients, methods Intact PTH and 25(OH)D were measured in 261 healthy controls (18-65 years, winter/summer). They were classified as 25(OH)D replete (50-153 nmol/l; n = 129) or deplete (8-50 nmol/l; n = 132). PTH was determined in 49 patients with surgically proven primary hyperparathyroidism. PTH thresholds for 95% specificities and corresponding sensitivities were computed from both 25(OH)D replete and deplete receiver operating characteristic (ROC) curves. The 95% bivariate reference ellipses, relating PTH to calcium for 25(OH)D replete and deplete controls, were compared to the PTH/calcium pairs of patients with primary hyperparathyroidism. Results Parathyroid hormone correlated with 25(OH)D (r = -0·3232; P < 0·0001). PTH normative values were 20% lower in 25(OH)D replete than deplete controls (P < 0·0001). PTH thresholds, providing 95% specificities for primary hyperparathyroidism diagnosis, were 7·6 pmol/l and 5·8 pmol/l, using ROC curves derived from 25(OH)D deplete or replete controls, respectively. Corresponding sensitivities were of 56%vs 88%, respectively (P < 0·05). The 95% PTH/calcium bivariate reference ellipses for?deplete and replete 25(OH)D controls differed, but the PTH/calcium pairs of patients with primary hyperparathyroidism did not overlap these ellipses. Conclusion For a given specificity, primary hyperparathyroidism diagnostic parathyroid hormone thresholds were lower and sensitivities higher using ROC curves, derived from 25(OH)D replete vs deplete controls. The 25(OH)D status does not affect the efficiency of primary hyperparathyroidism diagnosis, using bivariate PTH/calcium reference density ellipses. © 2012 Blackwell Publishing Ltd.

Zegers I.,European Commission | Keller T.,Acomed Statistik | Schreiber W.,Siemens AG | Sheldon J.,St Georges Hospital | And 7 more authors.
Clinical Chemistry | Year: 2010

BACKGROUND: The availability of a suitable matrix reference material is essential for standardization of the immunoassays used to measure serum proteins. The earlier serum protein reference material ERM-DA470 (previously called CRM470), certified in 1993, has led to a high degree of harmonization of the measurement results. A new serum protein material has now been prepared and its suitability in term of homogeneity and stability has been verified; after characterization, the material has been certified as ERM-DA470k/IFCC. METHODS: We characterized the candidate reference material for 14 proteins by applying a protocol that is considered to be a reference measurement procedure, by use of optimized immunoassays. ERM-DA470 was used as a calibrant. RESULTS: For 12 proteins [α2 macroglobulin (A2M), α1 acid glycoprotein (orosomucoid, AAG), α1 antitrypsin (α1-protease inhibitor, AAT), albumin (ALB), complement 3c (C3c), complement 4 (C4), haptoglobin (HPT), IgA, IgG, IgM, transferrin (TRF), and transthyretin (TTR)], the results allowed assignment of certified values in ERM-DA470k/IFCC. For CRP, we observed a bias between the lyophilized and liquid frozen materials, and for CER, the distribution of values was too broad. Therefore, these 2 proteins were not certified in the ERM-DA470k/IFCC. Different value transfer procedures were tested (open and closed procedures) and found to provide equivalent results. CONCLUSIONS: A new serum protein reference material has been produced, and values have been successfully assigned for 12 proteins. © 2010 American Association for Clinical Chemistry.

Hofmann E.,Universitatsklinikum | Medelnik J.,Universitatsklinikum | Keller T.,ACOMED Statistik | Steinhauser S.,Universitatsklinikum | Hirschfelder U.,Universitatsklinikum
Journal of Orofacial Orthopedics | Year: 2011

Aim: Precise, three-dimensional localization of impacted maxillary canines is central to their clinical management. Predicting precisely the crown's mesiodistal width is paramount in planning orthodontic treatment. The aim of this study was to verify the exact mesiodistal width of impacted canines via MSCT (multislice spiral computed tomography) examinations. Patients and methods: 3D MSCT images from 17 patients with a total of 24 impacted maxillary canines were taken to obtain the largest mesiodistal diameter using mesial and distal contact points. All existing maxillary canines were included in this study. Mesiodistal tooth width was also determined using callipers on a plaster model after canine eruption. Each measurement was taken twice by 3 observers after a 10-day interval. Statistical analysis entailed calculating and comparing the systematic error, intrarater and interrater standard deviations (Deming regression and ANOVA with random effects). Results: Comparison of the different methods revealed good agreement between the pre-eruption and post-eruption values regarding the canine's mesiodistal width. Total standard deviation was 0.16 mm for values obtained from MSCT measurements and 0.12 mm for those taken with callipers. For both methods intrarater measurement error differed by a factor of 2 (repeatability; model versus MSCT: 0.07 mm versus 0.12 mm), while interrater deviation did not differ significantly (reproducibility; model versus MSCT: 0.10 mm versus 0.10 mm). The reproducibility of our measurements whether taken on the model or with CT was below biological variability. Conclusions: The volumetric data from an MSCT system gives highly accurate information on the mesiodistal width of displaced canines. © 2011 Urban & Vogel.

Hanke S.,Friedrich - Alexander - University, Erlangen - Nuremberg | Hirschfelder U.,Friedrich - Alexander - University, Erlangen - Nuremberg | Keller T.,ACOMED Statistik | Hofmann E.,Friedrich - Alexander - University, Erlangen - Nuremberg
Journal of Cranio-Maxillofacial Surgery | Year: 2012

Objective: The aim of this study was to develop a reference system for multislice computed tomography (MSCT) images to determine of the location of impacted teeth in metric terms. Study design: The CT data of 17 patients with unilateral impacted maxillary canines were selected retrospectively from existing MSCT data sets. In a reference coordinate system, defined by anterior nasal spine (ANS), posterior nasal spine (PNS), and A-point, the axis length and the inclination of the canines were determined and impacted and non-impacted canines were compared. Results: There were significant differences between the impacted and non-impacted canines (p ≤ 0.0003) for all inclinations and the lengths in the x- and z-axes. The measurement of the inclination and sections of the impacted and non-impacted canine tooth axes showed sufficient repeatability and reproducibility. Conclusion: The coordinate system proved to be suitable for the exact metric localization of impacted teeth. © 2011 European Association for Cranio-Maxillo-Facial Surgery.

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