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Comparing the Cervista HPV HR test and Hybrid Capture 2 assay in a Dutch screening population: improved specificity of the Cervista HPV HR test by changing the cut-off.

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Comparing the Cervista HPV HR Test and Hybrid Capture 2 Assay in a Dutch Screening Population: Improved Specificity of the Cervista HPV HR Test by Changing the Cut-Off Aniek Boers1, Lorian Slagter-Menkema2, Bettien M. van Hemel2, Jerome L. Belinson3, Teus Ruitenbeek2, Henk J. Buikema2, Harry Klip1, Hilde Ghyssaert4, Ate G. J. van der Zee1, Geertruida H. de Bock5, G. Bea A. Wisman1, Ed Schuuring2* 1 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, 2 Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands, 3 Preventive Oncology International, Inc, Cleveland Heights and Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America, 4 Department of Pathology, AZ St Jan Brugge-Oostende, Brugge, Belgium, 5 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Abstract The diagnostic performance of the widely-used Cervista HPV HR test was compared to the Hybrid Capture 2 (HC2) test in a Dutch population-based cervical cancer screening program. In 900 scrapings of women with normal cytomorphology, specificity was 90% (95%CI: 87.84–91.87) for the Cervista HPV HR test and 96% (95%CI: 94.76–97.37) for the HC2 test with 93% agreement between both tests (k = 0.5, p,0.001). The sensitivity for CIN2+ using 65 scrapings of women with histological-confirmed CIN2+ was 91% (95%CI: 80.97–96.51) for the Cervista HPV HR test and 92% (95%CI: 82.94–97.43) for the HC2 test with 95% agreement between both tests (k = 0.7, p,0.001). Fifty-seven of 60 HC2 negative/Cervista positive cases tested HPV-negative with PCR-based HPV assays; of these cases 56% were defined as Cervista triple-positive with FOZ values in all 3 mixes higher than the second cut-off of 1.93 (as set by manufacturer). By setting this cut-off at 5.0, specificity improved significantly without affecting sensitivity. External validation of this new cut-off at 5.0 in triple-positive scrapings of women selected from the SHENCCASTII database revealed that 22/24 histological normal cases now tested HPV-negative in the Cervista HPV HR test, while CIN2+ lesions remained HPV-positive. The intra-laboratory reproducibility of the Cervista HPV HR test (n = 510) showed a concordance of 92% and 93% for cut-off 1.93 and 5.0 (k = 0.83 and k = 0.84, p,0.001) and inter-laboratory agreement of the Cervista HPV HR test was 90% and 93% for cut-off 1.93 and 5.0 (k = 0.80 and k = 0.85, p, 0.001). In conclusion, the specificity of the Cervista HPV HR test could be improved significantly by increasing the second cut-off from 1.93 to 5.0, without affecting the sensitivity of the test in a population-based screening setting. Citation: Boers A, Slagter-Menkema L, van Hemel BM, Belinson JL, Ruitenbeek T, et al. (2014) Comparing the Cervista HPV HR Test and Hybrid Capture 2 Assay in a Dutch Screening Population: Improved Specificity of the Cervista HPV HR Test by Changing the Cut-Off. PLoS ONE 9(7): e101930. doi:10.1371/journal.pone. 0101930 Editor: Fausto Baldanti, Fondazione IRCCS Policlinico San Matteo, Italy Received January 8, 2014; Accepted June 13, 2014; Published July 22, 2014 Copyright: ß 2014 Boers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: AB is supported by the Dutch Cancer Society (RUG-NKB2009-4577). The Cervista HPV HR test reagents were kindly provided by Hologic Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have read the journal’s policy and have the following conflicts: Ed Scuuring is a member of the scientific advisory board of Roche, Hologic and QCMD, received travel reimbursements from Roche, Abbott, Hologic Inc. and QCMD. AB, LSM, BvH received travel reimbursements from Hologic Inc. Jerome L. Belinson has received support in kind (reagents and testing) and funds for direct support and research, under the auspices of Preventive Oncology International Inc., from Hologic Inc., Qiagen, Gen-Probe, Merck Inc., BGI Shenzen, and GE Healthcare. The Cervista HPV HR test reagents were kindly provided by Hologic Inc. for this study. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. * Email: e.schuuring@umcg.nl Cervical carcinogenesis is strongly associated with high-risk human papillomavirus (hrHPV). Persistent infection with hrHPV can result in CIN lesions and neoplastic progression. Testing for hrHPV in cervical scrapings shows high sensitivity (94–97%) to detect CIN2+ lesions. However specificity, especially in younger women, is around 6% lower than with cytology [2,3]. Nowadays cervical cancer screening programs in many countries have combined cytomorphological examination and hrHPV testing [4,5]. The current Dutch screening program is primarily based on cytomorphological classification with hrHPV testing as a triage test for abnormal cytological results (ASCUS/LSIL) [4]. In the Introduction Population-based screening programs have led to a significant reduction of the incidence and mortality from cervical cancer [1]. In the Netherlands cytomorphological examination of cervical scrapings is used for early detection of cervical cancer and premalignant cervical intraepithelial neoplasia (CIN). Despite the high specificity (95–97%), a disadvantage of cytomorphological examination is the relatively low sensitivity (50–60%) for detection of high grade CIN lesions (CIN2/3) and cervical cancer [2]. PLOS ONE | www.plosone.org 1 July 2014 | Volume 9 | Issue 7 | e101930 Performance of the Cervista HPV HR Test Netherlands the population-based screening program will change to primary hrHPV screening in 2016 [6]. In primary screening hrHPV testing will be performed mostly on scrapings with no abnormalities, since the majority of the screening population is healthy. An optimal balance between the sensitivity and specificity of the hrHPV test is therefore important. At this moment numerous hrHPV tests are available, but only seven tests have been approved by the United States Food and Drug Administration (FDA) [7–9]. The first 2 and mostly used FDA approved HPV tests are the Hybrid Capture 2 (HC2) and the Cervista HPV HR assay [10]. The Digene HC2 test (Qiagen, Gaithersburg, MD) is a nucleic acid hybridization assay with signal amplification using microplate chemiluminescence for the detection of HPV DNA from 13 hrHPV types [11,12]. The Cervista HPV HR test (Hologic Inc., Madison, WI, USA) uses Invader chemistry, a signal amplification method for detection of specific nucleic acid sequences [13,14]. The Cervista HPV HR test detects 14 hrHPV types: HPV66 and the same 13 hrHPV types as detected by the HC2 test. Advantages of the Cervista HPV HR test compared to the HC2 test are; reduced sample volume required for testing (2 ml vs. 4 ml), the presence of an internal control which reduces the possibility of false-negative results due to insufficient DNA present in the sample and significant lower cross-reactivity to other HPV types [13,15,16]. Several studies analyzed the sensitivity and specificity for either the Cervista HPV HR test or the HC2 test [2,13,15,17–20], but studies comparing both assays on the same samples in a population-based screening setting are limited [21–23]. In this study, we compared the performance of the widely-used Cervista HPV HR test with the ‘‘golden standard’’ HC2 test on the same scrapings selected from the national population-based cervical cancer screening based on the international guidelines for HPV DNA testing in primary cervical cancer screening in women 30 years and older [24]. Samples with discordant results were analyzed using additional PCR-based HPV detecting assays. In addition, we determined the intra-laboratory reproducibility and inter-laboratory agreement of the Cervista HPV HR test. cytomorphological examination [2], we also included, of these 65 patients, 17 patients with a normal cytomorphological diagnosis [25]. These samples were selected from our research database of women who underwent a new cervical scraping before colposcopy. Cervista HPV HR method The Cervista HPV HR test (Hologic Inc., Madison, WI, USA) is a qualitative test detecting 14 hrHPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) [13,14]. The assay uses three separate oligonucleotide mixtures; Mix 1 (A5/A6 pool) contains probes for HPV 51, 56 and 66; mix 2 (A7 pool) probes for HPV 18, 39, 45, 59 and 68, and mix 3 (A9 pool) probes for HPV 16, 31, 33, 35, 52 and 58. In these three mixes, oligonucleotides for the human histone 2 gene (HIST2H2BE) are also present as an internal control for the presence of sufficient genomic DNA [14]. A signal to noise value (sample signal measured against signal from a No Target Control) is generated for each of the three mixes and is referred to as HPV Fold-Over-Zero (FOZ). The HPV FOZ ratio is calculated by dividing the highest FOZ value from any one of the three reaction mixtures by the lowest HPV FOZ value of the three mixtures. If the HPV FOZ ratio is equal to or greater than 1.525, the sample is considered positive for hrHPV [14]. Samples with mixed HPV infections might result in positive signals of similar intensity in two or three reaction wells. Therefore, if the HPV FOZ ratio is lower than 1.525, but the HPV FOZ values in all three mixes are larger than the second cut-off value at 1.93 (default setting), the sample is considered positive for hrHPV in the Cervista HPV HR test [14]. HC2 method The HC2 test is routinely used in our (ISO15189 certified) laboratory. The HC2 test is clinically validated and FDAapproved and detects 13 hrHPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). The HC2 test has previously been described extensively and results are interpreted as a ratio of relative light units (RLU/CO) to the positive control specimen [11,12]. Samples with an RLU/CO ratio .1.0 are considered positive for hrHPV. If the RLU/CO ratio ,1 the sample is negative for hrHPV infection and borderline RLU/CO ratios (1– 2.5) are re-tested. Materials and Methods Sample collection GP5+/6+ PCR and INNO-LiPA genotyping assay To compare the specificity of the Cervista HPV HR and HC2 test, 900 cytomorphological normal cervical scrapings (NILM) collected in PreservCyt of women between the ages of 30–60 years were randomly selected from the routine Dutch population-based screening program. Since women without cytomorphological abnormalities are not referred to the hospital for colposcopy, histology is not available for this group. To compare the specificity we only included women who also had a normal cervical scraping at the previous population-based screening 5 years prior and are therefore with the smallest chance of having an undetected CIN2+ lesion. Women with a history of (pre)malignant cervical lesions, abnormal cervical smears or any surgery in the area of the cervix as well as HIV-seropositive or pregnant women were excluded. Study-specific, uniquely numbered samples with more than 12 ml residual PreservCyt solution were collected to perform Cervista HPV HR and HC2 testing. To compare the sensitivity of the Cervista HPV HR and HC2 test, we randomly selected scrapings of women referred to the University Medical Center with abnormal cytology (.BMD) during routine population-based screening. All 65 women included had histological confirmed CIN2+ lesions. Since a considerable number of CIN2+ lesions are missed by routine PLOS ONE | www.plosone.org All 965 specimens were tested both with the Cervista HPV HR test and HC2 test. Cases with discordant results were retested for the presence of hrHPV using PCR-based HPV detection assays. The HPV-L1 consensus GP5+/6+ PCR was performed as previously described [26] on DNA extracted for the Cervista HPV HR test. Samples positive for the GP5+/6+ HPV-PCR were defined as true HPV-positive cases. The genotype of L1-HPV PCR positive cases was determined utilizing the INNO-LiPA HPV genotyping Extra assay [27,28]. For quality control, genomic DNA was amplified in a multiplex PCR containing a control gene primer set resulting in products of 100, 200, 300, 400 and 600 bp according to the BIOMED-2 protocol [29]. Only DNA samples with PCR products of 300 bp and larger were used for the detection of HPV. In silico analysis of the SHENCCASTII data To evaluate the effect of different second threshold values for the Cervista HPV HR test we used an external patient group with histological-confirmed normal and abnormal tissue. In silico analysis of the data available from the Shenzhen Cervical Cancer Screening Trial II (SHENCCASTII) [21] was kindly provided by 2 July 2014 | Volume 9 | Issue 7 | e101930 Performance of the Cervista HPV HR Test Biostatistics and Epidemiology (Cleveland Heights, Ohio) kindly provided by dr. S. Belinson. dr. S. Belinson. From the SHENCCASTII dataset a cohort comparable to our dataset was composed. This cohort contained data of women between the age 30–60 years who had a cervical scraping obtained by a physician (self-sampling scrapings were excluded) and HC2 as well as Cervista HPV HR results. All hrHPV positive women were referred for colposcopy and histological diagnosis was available. Results Sensitivity and specificity results in a Dutch screening population In scrapings of 65 women with histological confirmed CIN2+ lesions, sensitivity of the Cervista HPV HR test was 91% (95%CI: 80.97–96.51), for the HC2 test this was 92% (95%CI: 82.94– 97.43) (Table 1 and Table 2). Comparing both assays revealed a 95% agreement with a kappa of 0.7 (p,0.001). The specificity of the Cervista HPV HR and the HC2 test in 900 cytomorphological normal cervical scrapings was 90% (95%CI: 87.84–91.87) and 96% (95%CI: 94.76–97.37), respectively (Table 1 and Table 2). Comparison revealed an agreement of 93% between both tests with a kappa of 0.47 (p,0.001). The prevalence rate for detecting HPV in the cytomorphological negative population was 10% (90/899) using Cervista HPV HR test and 4% (34/900) using the HC2 test. Intra- and inter-laboratory reproducibility of the Cervista HPV HR test For intra- and inter-laboratory variability of the Cervista HPV HR test, 510 scrapings were selected. Seventy samples were selected from the 900 cytomorphological normal women from the population-based screening program. In the Netherlands women diagnosed with ASCUS or low-grade SIL are retested 6 months later using both cytomorphological assessment as well as hrHPV testing according the Dutch guidelines [4]. From these triage samples, 186 hrHPV-HC2 positive and 254 hrHPV-HC2 negative randomly-selected scrapings were included in this study according to the international guidelines for HPV DNA testing in primary cervical cancer screening in women 30 years an older by Meijer et al [24]. To determine the intra-laboratory reproducibility, all 510 samples were tested twice at different time points (at least 1 week difference) by the same experienced technician. For the interlaboratory agreement, 2 ml PreservCyt of the same samples were send to an independent reference-laboratory using Cervista HPV HR testing routinely (Department of Pathology, AZ St Jan Brugge-Oostende, Brugge, Belgium). All samples were randomlyrenumbered and provided to the reference-lab without knowledge of any results from the UMCG on cytomorphology or HPV status. Characterization of discordant results between the Cervista HPV HR and HC2 test Of the total 965 cases, 66 cases showed discordant results when comparing the Cervista HPV HR and HC2 test. One HC2negative case, showed a low gDNA outcome in the Cervista HPV HR test. Re-testing of this sample with the Cervista HPV HR test again showed a low gDNA outcome. This could be a false-negative result in the HC2 test, because of insufficient cells in the sample. Cytological examination confirmed low number of cells in the sample. Five cases were HC2 positive and Cervista negative (Table 3). Using the PCR-based consensus L1-HPV test (GP5+/6+ PCR) 4 out of 5 were positive. HPV typing according to the INNO-LiPA assay (Table 3 and Table S1) showed multiple HPV types in the tested samples. Most discordant cases (n = 60) reported HC2 negative/Cervista positive cases. The GP5+/6+ PCR was performed to determine if hrHPV DNA was in fact present in each of these samples (Table S1). Three cases were positive and genotyping with the INNOLiPA assay revealed HPV 39 and 56 (nr 34), HPV 16 (nr 35) and HPV 44 and 56 (nr 61). Thus the HC2 assay gave false-negative results in 3 of the 60 (5%) discordant cases tested. Remarkably, all other discordant cases tested negative with the GP5+/6+ PCR, resulting in false-positive results for the Cervista HPV HR test in 57 of the 60 cases (95%). Of these 57 HC2 negative/Cervista positive cases, 18 samples were positive in mix 1, 5 samples in mix 2, 2 samples in mix 3 and 32 samples in all 3 mixes (so-called Cervista triple-positive cases). Re-testing of these 57 discordant cases with the Cervista HPV HR test revealed 24 negative and 32 HPV positive cases (Table S1). Patient data Clinicopathological data of the patients such as age, medical history, cytological and histological results were retrieved from the hospital database and the patient’s pathology report, and entered into a separate, anonymous, password protected database. Protection of patient identity was guaranteed by assigning studyspecific unique equilibrium value of MeCpG steps (,+14 deg.) [31,44]. In comparison, methylation has a significantly lower stability cost when happening at major groove positions, such as 211 and 21 base pair from dyad (mutations 9 and 12), where the roll of the nucleosome bound conformation (+10 deg.) is more compatible with the equilibrium geometry of MeCpG steps. The nucleosome destabilizing effect of cytosine methylation increases with the number of methylated cytosines, following the same position dependence as the single methylations. The multiple-methylation case reveals that each major groove meth- PLOS Computational Biology | www.ploscompbiol.org 3 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning ylation destabilizes the nucleosome by around 1 kJ/mol (close to the average estimate of 2 kJ/mol obtained for from individual methylation studies), while each minor groove methylation destabilizes it by up to 5 kJ/mol (average free energy as single mutation is around 6 kJ/mol). This energetic position-dependence is the reverse of what was observed in a recent FRET/SAXS study [30]. The differences can be attributed to the use of different ionic conditions and different sequences: a modified Widom-601 sequence of 157 bp, which already contains multiple CpG steps in mixed orientations, and which could assume different positioning due to the introduction of new CpG steps and by effect of the methylation. The analysis of our trajectories reveals a larger root mean square deviation (RMSD) and fluctuation (RMSF; see Figures S2– S3 in Text S1) for the methylated nucleosomes, but failed to detect any systematic change in DNA geometry or in intermolecular DNA-histone energy related to methylation (Fig. S1B, S1C, S4–S6 in Text S1). The hydrophobic effect should favor orientation of the methyl group out from the solvent but this effect alone is not likely to justify the positional dependent stability changes in Figure 2, as the differential solvation of the methyl groups in the bound and unbound states is only in the order of a fraction of a water molecule (Figure S5 in Text S1). We find however, a reasonable correlation between methylation-induced changes in hydrogen bond and stacking interactions of the bases and the change in nucleosome stability (see Figure S6 in Text S1). This finding suggests that methylation-induced nucleosome destabilization is related to the poorer ability of methylated DNA to fit into the required conformation for DNA in a nucleosome. Changes in the elastic deformation energy between methylated and un-methylated DNA correlate with nucleosomal differential binding free energies To further analyze the idea that methylation-induced nucleosome destabilization is connected to a worse fit of methylated DNA into the required nucleosome-bound conformation, we computed the elastic energy of the nucleosomal DNA using a harmonic deformation method [36,37,44]. This method provides a rough estimate of the energy required to deform a DNA fiber to adopt the super helical conformation in the nucleosome (full details in Suppl. Information Text S1). As shown in Figure 2, there is an evident correlation between the increase that methylation produces in the elastic deformation energy (DDE def.) and the free energy variation (DDG bind.) computed from MD/TI calculations. Clearly, methylation increases the stiffness of the CpG step [31], raising the energy cost required to wrap DNA around the histone octamers. This extra energy cost will be smaller in regions of high positive roll (naked DNA MeCpG steps have a higher roll than CpG steps [31]) than in regions of high negative roll. Thus, simple elastic considerations explain why methylation is better tolerated when the DNA faces the histones through the major groove (where positive roll is required) that when it faces histones through the minor groove (where negative roll is required). Nucleosome methylation can give rise to nucleosome repositioning We have established that methylation affects the wrapping of DNA in nucleosomes, but how does this translate into chromatin structure? As noted above, accumulation of minor groove methylations strongly destabilizes the nucleosome, and could trigger nucleosome unfolding, or notable changes in positioning or phasing of DNA around the histone core. While accumulation of methylations might be well tolerated if placed in favorable positions, accumulation in unfavorable positions would destabilize the nucleosome, which might trigger changes in chromatin structure. Chromatin could in fact react in two different ways in response to significant levels of methylation in unfavorable positions: i) the DNA could either detach from the histone core, leading to nucleosome eviction or nucleosome repositioning, or ii) the DNA could rotate around the histone core, changing its phase to place MeCpG steps in favorable positions. Both effects are anticipated to alter DNA accessibility and impact gene expression regulation. The sub-microsecond time scale of our MD trajectories of methylated DNAs bound to nucleosomes is not large enough to capture these effects, but clear trends are visible in cases of multiple mutations occurring in unfavorable positions, where unmethylated and methylated DNA sequences are out of phase by around 28 degrees (Figure S7 in Text S1). Due to this repositioning, large or small, DNA could move and the nucleosome structure could assume a more compact and distorted conformation, as detected by Lee and Lee [29], or a slightly open conformation as found in Jimenez-Useche et al. [30]. Using the harmonic deformation method, we additionally predicted the change in stability induced by cytosine methylation for millions of different nucleosomal DNA sequences. Consistently with our calculations, we used two extreme scenarios to prepare our DNA sequences (see Fig. 3): i) all positions where the minor grooves contact the histone core are occupied by CpG steps, and ii) all positions where the major grooves contact the histone core are occupied by CpG steps. We then computed the elastic energy required to wrap the DNA around the histone proteins in unmethylated and methylated states, and, as expected, observed that methylation disfavors DNA wrapping (Figure 3A). We have rescaled the elastic energy differences with a factor of 0.23 to match the DDG prediction in figure 2B. In agreement with the rest of our results, our analysis confirms that the effect of methylation is position-dependent. In fact, the overall difference between the two extreme methylation scenarios (all-in-minor vs all-in-major) is larger than 60 kJ/mol, the average difference being around 15 kJ/ mol. We have also computed the elastic energy differences for a million sequences with CpG/MeCpG steps positioned at all possible intermediate locations with respect to the position (figure 3B). The large differences between the extreme cases can induce rotations of DNA around the histone core, shifting its phase to allow the placement of the methylated CpG steps facing the histones through the major groove. It is illustrative to compare the magnitude of CpG methylation penalty with sequence dependent differences. Since there are roughly 1.5e88 possible 147 base pairs long sequence combinations (i.e., (4n+4(n/2))/2, n = 147), it is unfeasible to calculate all the possible sequence effects. However, using our elastic model we can provide a range of values based on a reasonably large number of samples. If we consider all possible nucleosomal sequences in the yeast genome (around 12 Mbp), the energy difference between the best and the worst sequence that could form a nucleosome is 0.7 kj/mol per base (a minimum of 1 kJ/mol and maximum of around 1.7 kJ/mol per base, the first best and the last worst sequences are displayed in Table S3 in Text S1). We repeated the same calculation for one million random sequences and we obtained equivalent results. Placing one CpG step every helical turn gives an average energetic difference between minor groove and major groove methylation of 15 kJ/ mol, which translates into ,0.5 kJ/mol per methyl group, 2 kJ/ mol per base for the largest effects. Considering that not all nucleosome base pair steps are likely to be CpG steps, we can conclude that the balance between the destabilization due to CpG methylation and sequence repositioning will depend on the PLOS Computational Biology | www.ploscompbiol.org 4 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning Figure 3. Methylated and non-methylated DNA elastic deformation energies. (A) Distribution of deformation energies for 147 bplong random DNA sequences with CpG steps positioned every 10 base steps (one helical turn) in minor (red and dark red) and major (light and dark blue) grooves respectively. The energy values were rescaled by the slope of a best-fit straight line of figure 2, which is 0.23, to por la lectura a través de la lectura de la prensa. La educación en los medios las fuerzas dispersas en función de los soportes mediáticos y orientarse más hacia la educación en medios que al dominio adquiere pleno derecho y entidad en la sección sexta titulada «competencias sociales y cívi- técnico de los aparatos. cas» que indica que «los alum- nos deberán ser capaces de juz- gar y tendrán espíritu crítico, lo que supone ser educados en los las programaciones oficiales, ya que, a lo largo de un medios y tener conciencia de su lugar y de su influencia estudio de los textos, los documentalistas del CLEMI en la sociedad». han podido señalar más de una centena de referencias a la educación de los medios en el seno de disciplinas 4. Un entorno positivo como el francés, la historia, la geografía, las lenguas, Si nos atenemos a las cifras, el panorama de la las artes plásticas : trabajos sobre las portadas de educación en medios es muy positivo. Una gran ope- prensa, reflexiones sobre temas mediáticos, análisis de ración de visibilidad como la «Semana de la prensa y publicidad, análisis de imágenes desde todos los ángu- de los medios en la escuela», coordinada por el CLE- los, reflexión sobre las noticias en los países europeos, MI, confirma año tras año, después de 17 convocato- información y opinión rias, el atractivo que ejerce sobre los profesores y los Esta presencia se constata desde la escuela mater- alumnos. Concebida como una gran operación de nal (2 a 6 años) donde, por ejemplo, se le pregunta a complementariedad entre la escuela y los profesiona- los niños más pequeños si saben diferenciar entre un les de los medios, alrededor del aprendizaje ciudada- periódico, un libro, un catálogo, a través de activida- no de la comunicación mediática, este evento moviliza des sensoriales, si saben para qué sirve un cartel, un durante toda una semana un porcentaje elevado de periódico, un cuaderno, un ordenador si son capa- centros escolares que representan un potencial de 4,3 ces de reconocer y distinguir imágenes de origen y de millones de alumnos (cifras de 2006). Basada en el naturaleza distintas. Podríamos continuar con más voluntariado, la semana permite desarrollar activida- ejemplos en todos los niveles de enseñanza y práctica- des más o menos ambiciosas centradas en la introduc- Páginas 43-48 ción de los medios en la vida de la escuela a través de la instalación de kioscos, organización de debates con profesionales y la confección por parte de los alumnos de documentos difundidos en los medios profesionales. Es la ocasión de dar un empujón a la educación en medios y de disfrutarlos. Los medios –un millar en 2006– se asocian de maneras diversas ofreciendo ejemplares de periódicos, acceso a noticias o a imágenes, proponiendo encuentros, permitiendo intervenir a los jóvenes en sus ondas o en sus columnas Esta operación da luz al trabajo de la educación en medios y moviliza a los diferentes participantes en el proyecto. 5. La formación de los docentes La formación es uno de los pilares principales de la educación en los medios. Su función es indispensable ya que no se trata de una disciplina, sino de una enseñanza que se hace sobre la base del voluntariado y del compromiso personal. Se trata de convencer, de mostrar, de interactuar. En primer lugar es necesario incluirla en la formación continua de los docentes, cuyo volumen se ha incrementado desde 1981 con la aparición de una verdadera política de formación continua de personal. Es difícil dar una imagen completa del volumen y del público, pero si nos atenemos a las cifras del CLEMI, hay más de 24.000 profesores que han asistido y se han involucrado durante 2004-05. 5.1. La formación continua En la mayoría de los casos, los profesores reciben su formación en contextos cercanos a su centro de trabajo, o incluso en este mismo. Después de una política centrada en la oferta que hacían los formadores, se valora más positivamente la demanda por parte del profesorado, ya que sólo así será verdaderamente fructífera. Los cursos de formación se repartieron en varias categorías: desde los formatos más tradicionales (cursos, debates, animaciones), hasta actividades de asesoramiento y de acompañamiento, y por supuesto los coloquios que permiten un trabajo en profundidad ya que van acompañados de expertos investigadores y profesionales. Citemos, por ejemplo en 2005, los coloquios del CLEMI-Toulouse sobre el cine documental o el del CLEMI-Dijon sobre «Políticos y medios: ¿connivencia?». Estos coloquios, que forman parte de un trabajo pedagógico regular, reagrupan a los diferentes participantes regionales y nacionales alrededor de grandes temas de la educación en medios y permiten generar nuevos conocimientos de aproximación y una profundización. Páginas 43-48 Hay otro tipo de formación original que se viene desarrollando desde hace menos tiempo, a través de cursos profesionales, como por ejemplo, en el Festival Internacional de Foto-periodismo «Visa para la imagen», en Perpignan. La formación se consolida en el curso, da acceso a las exposiciones, a las conferencias de profesionales y a los grandes debates, pero añade además propuestas pedagógicas y reflexiones didácticas destinadas a los docentes. Estas nuevas modalidades de formación son también consecuencia del agotamiento de la formación tradicional en las regiones. Los contenidos más frecuentes en formación continua conciernen tanto a los temas más clásicos como a los cambios que se están llevando a cabo en las prácticas mediáticas. Así encontramos distintas tendencias para 2004-05: La imagen desde el ángulo de la producción de imágenes animadas, el análisis de la imagen de la información o las imágenes del J.T. La prensa escrita y el periódico escolar. Internet y la información en línea. Medios y educación de los medios. 5.2 La formación inicial La formación inicial está aun en un grado muy ini- cial. El hecho de que la educación en medios no sea una disciplina impide su presencia en los IUFM (Institutos Universitarios de Formación de Maestros) que dan una prioridad absoluta a la didáctica de las disciplinas. En 2003, alrededor de 1.400 cursillistas sobre un total de 30.000 participaron en un momento u otro de un módulo de educación en medios. Estos módulos se ofrecen en función del interés que ese formador encuentra puntualmente y forman parte a menudo de varias disciplinas: documentación, letras, historia-geografía Estamos aún lejos de una política concertada en este dominio. La optativa «Cine-audiovisual» ha entrado desde hace muy poco tiempo en algunos IUFM destinada a obtener un certificado de enseñanza de la opción audiovisual y cine. Internet tiene cabida también en los cursos de formación inicial, recientemente con la aparición de un certificado informático y de Internet para los docentes, dirigido más a constatar competencias personales que a valorar una aptitud para enseñarlos. 6. ¿Y el futuro? El problema del futuro se plantea una vez más por la irrupción de nuevas técnicas y nuevos soportes. La difusión acelerada de lo digital replantea hoy muchas cuestiones relativas a prácticas mediáticas. Muchos Comunicar, 28, 2007 47 Comunicar, 28, 2007 Enrique Martínez-Salanova '2007 para Comunicar 48 trabajos que llevan el rótulo de la educación en medios solicitan una revisión ya que los conceptos cambian. La metodología elaborada en el marco de la educación en medios parece incluso permitir la inclinación de la sociedad de la información hacia una sociedad del conocimiento, como defiende la UNESCO. En Francia, se necesitaría unir las fuerzas dispersas en función de los soportes mediáticos y orientarse más hacia la educación en medios que al dominio técnico de los aparatos. Los avances recientes en el reconocimiento de estos contenidos y las competencias que supondrían podrían permitirlo. Referencias CLEMI/ACADEMIE DE BORDEAUX (Ed.) (2003): Parcours médias au collège: approches disciplinaires et transdisciplinaires. Aquitaine, Sceren-CRDP. GONNET, J. (2001): Education aux médias. Les controverses fécondes. Paris, Hachette Education/CNDP. SAVINO, J.; MARMIESSE, C. et BENSA, F. (2005): L’éducation aux médias de la maternelle au lycée. Direction de l’Enseignement Scolaire. Paris, Ministère de l’Education Nationale, Sceren/CNDP, Témoigner. BEVORT, E. et FREMONT, P. (2001): Médias, violence et education. Paris, CNDP, Actes et rapports pour l’éducation. – www.clemi.org: fiches pédagogiques, rapports et liens avec les pages régionales/académiques. – www.ac-nancy-metz.fr/cinemav/quai.html: Le site «Quai des images» est dédié à l’enseignement du cinéma et de l’audiovisuel. – www.france5.fr/education: la rubrique «Côté profs» a une entrée «education aux médias». – www.educaunet.org: Programme européen d’éducation aux risques liés à Internet. dResedfeleexliobnuetsacón Páginas 43-48
Comparing the Cervista HPV HR test and Hybrid Capture 2 assay in a Dutch screening population: improved specificity of the Cervista HPV HR test by changing the cut-off.
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Comparing the Cervista HPV HR test and Hybrid Capture 2 assay in a Dutch screening population: improved specificity of the Cervista HPV HR test by changing the cut-off.

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