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Pone.0032122 1.7Point-of-Care Test for Detection of Urogenital Chlamydiain Women Shows Low Sensitivity. A PerformanceEvaluation Study in Two Clinics in Suriname Jannie J. van der Helm1, Leslie O. A. Sabajo2, Antoon W. Grunberg3, Servaas A. Morre´4,5, Arjen G. C. L.
Speksnijder6, Henry J. C. de Vries1,7,8,9* 1 STI Outpatient Clinic, Cluster Infectious Diseases, Public Health Service Amsterdam, Amsterdam, The Netherlands, 2 Dermatological Service, Ministry of Health, Paramaribo, Suriname, 3 Lobi Foundation, Paramaribo, Suriname, 4 VU University Medical Center, Amsterdam, The Netherlands, 5 Institute of Public Health Genomics, Department of Genetics and Cell Biology, Research Institutes CAPHRI and GROW, Faculty of Health, Medicine & Life Sciences, University of Maastricht, Maastricht, The Netherlands, 6 Public Health Laboratory, Cluster Infectious Diseases, Public Health Service Amsterdam, Amsterdam, The Netherlands, 7 Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 8 Centre for Infections and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 9 Centre for Infectious Disease Control, National Institute of Public Health and the Environment, Bilthoven, The Netherlands Background: In general, point-of-care (POC) tests for Chlamydia trachomatis (Ct) show disappointing test performance,especially disappointing sensitivity results. However, one study sponsored by the manufacturer (Diagnostics for the RealWorld) reported over 80% sensitivity with their Chlamydia Rapid Test (CRT). We evaluated the performance of this CRT in anon–manufacturer-sponsored trial.
Methods: Between July 2009 and February 2010, we included samples from 912 women in both high- and low-risk clinicsfor sexually transmitted infections (STIs) in Paramaribo, Suriname. Sensitivity, specificity, positive- and negative predictivevalues (PPV and NPV) for CRT compared to NAAT (Aptima, Gen-Probe) were determined. Quantitative Ct load and humancell load were determined in all CRT and/or NAAT positive samples.
Results: CRT compared to NAAT showed a sensitivity and specificity of 41.2% (95% CI, 31.9%–50.9%) and 96.4% (95% CI,95.0%–97.5%), respectively. PPV and NPV were 59.2% (95% CI, 47.5%–70.1%) and 92.9% (95% CI, 91.0%–94.5%), respectively.
Quantitative Ct bacterial load was 73 times higher in NAAT-positive/CRT-positive samples compared to NAAT-positive/CRT-negative samples (p,0.001). Human cell load did not differ between true-positive and false-negative CRT results (p = 0.835).
Sensitivity of CRT in samples with low Ct load was 12.5% (95% CI, 5.2%–24.2%) and in samples with high Ct load 73.5% (95%CI, 59.9%–84.4%).
Conclusions: The sensitivity of CRT for detecting urogenital Ct in this non–manufacturer-sponsored study did not meet theexpectations as described previously. The CRT missed samples with a low Ct load. Improved POC are needed as meaningfuldiagnostic to reduce the disease burden of Ct.
Citation: van der Helm JJ, Sabajo LOA, Grunberg AW, Morre´ SA, Speksnijder AGCL, et al. (2012) Point-of-Care Test for Detection of Urogenital Chlamydia inWomen Shows Low Sensitivity. A Performance Evaluation Study in Two Clinics in Suriname. PLoS ONE 7(2): e32122. doi:10.1371/journal.pone.0032122 Editor: Deborah Dean, University of California San Francisco, University of California, Berkeley, and the Children’s Hospital Oakland Research Institute, UnitedStates of America Received November 3, 2011; Accepted January 19, 2012; Published February 29, 2012 Copyright: ß 2012 van der Helm et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Research and Development fund of the Municipal Health Service of Amsterdam [project no 2369 and 2371] and AGIShealthcare insurance [RVVZ no 1417000]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of themanuscript.
Competing Interests: The authors have declared that no competing interests exist.
tion Tests (NAAT), but they are expensive and requiresophisticated laboratory conditions . This makes NAAT Urogenital chlamydia is the most prevalent, curable bacterial unsuitable for the detection of Ct for most low-resource settings sexually transmitted infection (STI) worldwide , with a . Therefore the World Health organization (WHO) has significant public health burden, especially in young women .
launched a priority program that is designated to develop The causative bacterium, Chlamydia trachomatis (Ct) causes a high affordable and reliable point-of-care (POC) tests for STIs that rate of asymptomatic infections  and is associated with adverse are predominant in low resource countries [http://www.who.int/ outcomes like infertility, ectopic pregnancy and pelvic inflamma- std_diagnostics]. In this program, WHO has formulated the tory disease (PID) . To reduce transmission and late ASSURED criteria that POC tests have to meet: Affordable, complications, active case finding and early treatment are critical Sensitive, Specific, User-friendly, Robust and rapid, Equipment- strategies. The standard diagnostics are Nucleic Acid Amplifica- free, Deliverable to those who need them . The POC test result February 2012 | Volume 7 | Issue 2 | e32122 should be readily available, while the patient waits, to ensure Specimen collection and testing procedures prompt treatment. This is especially important where patient Nurse-collected vaginal swabs were obtained blindly for the return for treatment is low. It is estimated that a POC test of Chlamydia Rapid Test (CRT) (Diagnostics for the Real World moderate sensitivity (63%) combined with immediate treatment (Europe), Cambridge, UK) and NAAT (Aptima, Gen-Probe, San on-site may lead to the treatment of more infected individuals than Diego, USA) testing using a cross-over model. This means that in an ultra-sensitive and specific NAAT alone when patient return is the first half of the included women the swab for the CRT was taken low . Moreover, counselling messages are most efficient when a first and the second of the included women NAAT was taken first.
diagnosis can be communicated during the same consultation .
Nurses were trained to collect the swabs before routine speculum These advantages are relevant for industrialized countries as well, examination was performed. A minimum period of 10 times for even if POC tests have a lower sensitivity than standard NAAT.
CRT and 10 seconds for NAAT of contact between the tip of the To date, POC tests for urogenital chlamydia show disappoint- swab and the vaginal wall in a rotating motion was ensured. CRT ing test characteristics, especially low sensitivity. In a recent was immediately performed according to the manufacturer’s evaluation, three POC tests for urogenital chlamydia, currently on instructions on-site in the laboratory. All technicians that performed the market, showed poor sensitivity between 12% and 17% in a the CRT were trained with proficiency panels as provided and non–manufacturer-sponsored clinical study . In contrast, one instructed by the manufacturer. Technicians did not receive POC test for urogenital chlamydia (Diagnostics for the Real information about the participant. The test results were interpreted World, Cambridge, UK) especially developed for low-resource and recorded by two laboratory technicians separately. CRT results countries has an asserted sensitivity of over 80% . A were defined as indeterminate when the laboratory technicians manufacturer-sponsored diagnostic field study in the Philippines reported discordant results or when CRT failed (i.e. control line did revealed sensitivities of 71% and 87% among women at high risk not appear). The samples for NAAT testing were collected and low risk for STI, respectively . Suriname, South America, according to the manufacturer’s instructions, and shipped to the is a low-resource country and affordable and reliable diagnostics to Public Health Laboratory in Amsterdam where they were tested detect Ct are urgently needed. Therefore, we aimed to evaluate within 50 days after collection. NAAT test results were communi- the performance of this promising POC test in two outpatient cated with the two recruitment sites in Suriname and participants clinics in Suriname, with the objective to use this test for with a positive-Ct NAAT were treated with doxycycline 100 mg bid intervention of the chlamydia epidemic.
for 7 days at Lobi Foundation and 10 days bid at theDermatological Service or, in case of (possible) pregnancy, with a single 1000 mg oral dose of azithromycin.
The study was approved by the ethical committee of the The CRT was performed as described previously . Version Ministry of Health of the Republic of Suriname (VG010-2007) 6.1 of the Chlamydia Rapid Test (Professional use) (P/N 1200-20) and the ethical committee of the Academic Medical Centre, instructions for use (C03-0008) was used. Shortly, each swab was University of Amsterdam, the Netherlands (MEC07/127). Patients subjected to extraction by sequential addition of 400 ml of reagent were recruited at two sites in Paramaribo, Suriname: 1, 300 ml of reagent 2, and 100 ml of reagent 3 to the swab in a The Dermatological Service, an integrated outpatient clinic tapered sample preparation tube, with gentle mixing between that offers free-of-charge examination and treatment of STIs additions. The sample preparation reagents were administered and infectious skin diseases like leprosy and leishmaniasis. All with unit dose pipettes. The extraction tube was then capped and consecutive women who visited for an STI check-up were used as a dropper to deliver 5 drops (approximately 100 ml) of the asked to participate in the study and were considered to be at extracted sample to a tube containing the lyophilized amplification and detection reagents. The resulting mixture was agitated gentlyuntil a clear pink solution was obtained, after which the test strip, The Lobi Foundation is a center for birth control and sexual coated with a monoclonal antibody to chlamydial lipopolysaccha- health. As women who visit this clinic do not attend primarily ride (LPS) and including a procedural control, was added to the to be checked for STI, these participants were considered to solution and allowed to stand for 25 minutes before the result was read. Each swab was subjected to one extraction. The test strip Recruitment took place between July 2009 and February 2010.
was used in the interpretation of the result; a clearly visible test line Exclusion criteria were: use of antibiotics in the past 7 days, age indicated a positive result, provided that the control line was also younger than 18 years and previous participation. After written informed consent, patients were given a unique code toparticipate anonymously. Participants were interviewed about demographic characteristics, including self-reported ethnicity as For NAAT testing, the monospecific Aptima chlamydia assay Suriname is a multiethnic society, with many ethnic groups such for the detection of Chlamydia trachomatis rRNA (Gen-Probe Inc., as Creoles and Maroons (both descendants from the African San Diego, USA) was used with the accompanying vaginal swab diaspora due to slave trade), Hindustani, Javanese, and Chinese specimen collection kit. The protocols described in the package (all descendants from labor immigrants), Caucasians (descendants inserts were followed. Technicians performing NAAT were from Dutch farmers), indigenous Amerindian people and Mixed blinded to the results of the POC-Ct and did not receive clinical race persons. Moreover, participants were asked about willing- information. This NAAT is an FDA-approved commercial test ness to wait for POC test results, although in our study and was used to estimate the Ct prevalence at both study sites.
participants did not receive the results from POC, and if theyused any products for vaginal hygiene like douches, herbs, or other home products, and if so, in what frequency. Data were Quantitative Ct load was determined for samples with a discrepant test result between CRT and NAAT, and for samples February 2012 | Volume 7 | Issue 2 | e32122 that tested positive for CRT as well as for NAAT using a real-time excluded from the CRT performance evaluation due to either PCR targeting the cryptic plasmid . Ct load was expressed as discrepancy in CRT result between two lab technicians (n = 3) or inclusion forming units (IFU) based on defined serial dilutions of Ct cultured in human cells with over .90% infected HeLa cells of General characteristics of the 912 women included in the CRT 100 IFU to 0.001 IFU taking into account also DNA from non- performance evaluation are shown in Table 1. Their median age viable Ct particles. The human cell load was assessed by was 30 years (IQR 25–36), 336 (36.9%) were of Creole/Maroon determination of human HLA copies in combination with a ethnicity and 229 (25.1%) were of Hindustani ethnicity. Twenty- defined serial dilution of quantified human DNA using the fol- one (2.3%) women reported having had sex for money or goods.
lowing primer probe combination: HLA-F 59-TTG-TAC-CAG- Almost all women 900 (98.7%) would wait for the CRT test result TTT-TAC-GGT-CCC-39 HLA-R 59- TGG-TAG-CAG-CGG- if the test were a standard offering in their clinic. Of these women, TAG-AGT-TG,-3 and HLA-Probe 59-FAM- TTC TAC GTG 660 (73.3%) would be willing to wait for a maximum of half an GAC CTG GAG AGG AAG GAG -BHQ1-39. By using a hour to receive the results, the other 240 (26.7%) would be willing chlamydial and a human target, the average chlamydial/human cell ratio, and IFU/swab were calculated .
Ct prevalence and CRT performance results Ct prevalence was 20.8% in the high-risk population (visiting To evaluate the performance of CRT compared to NAAT the Dermatological Service) and 9.2% in the low-risk population sensitivity, specificity, positive predictive value (PPV) and negative (visiting Lobi Foundation). Combining the results of the two sites, predictive value (NPV) were calculated using standard methods.
the sensitivity and specificity of the CRT in identifying Ct Specimens with indeterminate results by CRT were excluded. An compared to NAAT were 41.2% (95% CI, 31.9%–50.9%) and independent t-test was used to compare log-transformed Ct loads 96.4% (95% CI, 95.0%–97.5%), respectively. PPV of the CRT between true-positive and false-negative CRT results. Analyses was 59.2% (95% CI, 47.5%–70.1%) and NPV was 92.9% (95% were performed with SPSS package version 19.0 (SPSS Inc., CI, 91.0%–94.5%). Sensitivity and specificity of CRT compared to NAAT were comparable for the high-risk population (39.4% The study has been reported according to the STARD checklist and 94.4%) and the low-risk population (42.0% and 96.8%) for the reporting of studies of diagnostic accuracy.
Quantitative Ct bacterial load and human HLA were assessed for the samples that showed discrepant results for CRT and In total, 1019 women were asked to participate in the study, of NAAT (n = 89) and for samples that were CRT and NAAT whom 917 were included and 102 did not meet the inclusion positive (n = 42). Ct bacterial load could be detected in 99/131 criteria or declined to participate (Figure 1). Five women were samples and human HLA in 126/131 samples. Of the 42 samples Figure 1. Flow chart of specimen collection for the evaluation of a Chlamydia Rapid Test test as diagnostic for urogenital chlamydiain women at two study sites in Paramaribo, Suriname, from July 2009 to February 2010. NAAT; Aptima chlamydia single test, Genprobe(control test) CRT; Chlamydia Rapid Test, Diagnostics for the Real World (evaluated test).
doi:10.1371/journal.pone.0032122.g001 February 2012 | Volume 7 | Issue 2 | e32122 Table 1. General characteristics of the 912 women included in the evaluation of a Chlamydia Rapid Test as diagnostic forurogenital chlamydia in women at two study sites in Paramaribo, Suriname, from July 2009 to February 2010.
Maximum time these women are willing to wait Frequency of cleansing among those who practice vaginal cleansing IQR; interquartile range.
doi:10.1371/journal.pone.0032122.t001 Table 2. Performance results of the Diagnostics for the Real World Chlamydia Rapid Test (CRT) compared to NAAT (Aptimachlamydia single test).
Evaluation of a CRT as diagnostic for urogenital chlamydia in women at two study sites in Paramaribo, Suriname, from July 2009 to February 2010.
PPV; positive predictive value.
NPV; negative predictive value.
95% CI; 95% confidence interval.
doi:10.1371/journal.pone.0032122.t002 February 2012 | Volume 7 | Issue 2 | e32122 that tested positive for CRT and NAAT, quantitative Ct bacterial load was detected in all 42 samples and human HLA in 39samples. Of the 60 samples that tested CRT negative and NAAT We found a disappointingly low clinical sensitivity of 42.0% and positive, quantitative Ct bacterial load was detected in 55 samples 39.4% of the CRT in low-risk and high-risk Surinamese women, and human HLA in all 60 samples. Of the 29 samples that tested respectively, compared to the sensitivity of 86.8% in low-risk CRT positive and NAAT negative, quantitative Ct bacterial load women and 71% in high-risk women in the Philippines, reported was detected in 2 samples and human HLA in 27 samples earlier in a study supported by the manufacturer . The discrepancy might partly be explained by the use of a differentreference test. Where we used Gen-Probe’s Aptima platform as a Quantitative Ct bacterial load was 73 times higher in NAAT- reference test, in the Philippines study the Roche Amplicor (Roche positive/CRT-positive samples (geometric mean 120 IFU) com- Molecular Systems, Branchburg, NJ) was used. Although current pared to NAAT-positive/CRT-negative samples (geometric mean generation NAATs have comparable sensitivities, NAAT could be 1.64 IFU, p,0.001). Human DNA concentration did not differ more sensitive than Roche Amplicor . A somewhat lower sensitivity of CRT in our study could be expected with a more (p = 0.835). The average chlamydial/human cell load ratio (Ct sensitive control test, but this does not explain the large difference concentration) was 60 times higher in NAAT-positive samples in sensitivity found in the Philippine study and our results.
where CRT detected Ct infection (geometric mean 0.32 IFU/ Another explanation for the lower sensitivity we found could be human cell) compared to loads that CRT did not detect (geometric attributed to a different wash-out period for antibiotic use between mean 0.0053 IFU/human cell, p,0.001). Quantitative HLA load the two studies. We excluded women who used antibiotics in the was comparable for NAAT-positive/CRT-positive samples (geo- last 7 days, while in the Philippines study women who used metric mean 344 cells) compared to NAAT-negative/CRT- antibiotics in the previous month were excluded. Time to positive samples (geometric mean 451 cells, p = 0.424).
clearance of LPS antigen, which is targeted by the CRT, might Quantitative Ct loads were comparable for women reporting be shorter after antibiotic use than time to clearance of Ct rRNA, symptoms like vaginal discharge, irregular menstruation, pain which is targeted by NAAT . This could have caused the during intercourse, lower abdominal pain or dysuria and women occurrence of false-positive NAAT samples, and consequently without the specific symptom (data not shown). Women visiting more false-negative CRT samples could be expected. Low the high-risk STI clinic had comparable quantitative Ct loads with sensitivity of the CRT due to inadequate collection resulting in a those visiting the low-risk clinic (p = 0.525). Sensitivity of the CRT low sample yield could be ruled out since the human cell load in was comparable for those who practiced any vaginal hygienic samples with true-positive and false-negative CRT results was measures, 37.5% (95% CI, 23.6%–53.1%), compared to those comparable. The CRT had a 96.4% specificity. False-positive who did not practice vaginal cleansing, 43.3% (95% CI, 31.3%– CRT results could have been caused by cross reactivity with C.
56.0%). When comparing women who practice vaginal cleansing ptsittaci or C. pneumoniae as described in the manufacturers manual.
frequently, at least once a week, with those who cleanse less than Yet infections with these organisms in the urogenital tract in once weekly, sensitivity of CRT yields comparable results, 39.1% humans are uncommon [17,18]. As a false positive chlamydia (95% CI, 21.1%–59.8%) and 27.3% (95% CI, 7.5%–57.8%), diagnosis can have serious adverse social consequences a specificity of 96,4% is undesirable, especially in low prevalent settings. The Based on the overall median Ct load, NAAT-positive samples CRT in our study had a few modifications compared to the study were divided in two groups with either a low- (range 0.006–12.5 in the Philippines. We used unit dose pipettes instead of unit dose IFU) or high-grade quantitative bacterial Ct load (range 13.5– vials. Also, the nitrocellulose membrane was changed by the 6470 IFU). In the low-grade bacterial load group, the CRT manufacturer and according to the manual, only one dipstick had sensitivity was 12.5% (95% CI, 5.2%–24.2%), whereas in the high- to be used to interpret the results. However, when a test is renewed grade Ct load group the sensitivity was 73.5% (95% CI, 59.9%– one might expect at least comparable diagnostic characteristics Table 3. C. trachomatis quantitative bacterial load and human cell load measurements in concordant and discordant samples withNAAT (Aptima chlamydia single test) and the Diagnostics for the Real World Chlamydia Rapid Test (CRT).
Geometric mean human cell load (HLA copy) Concentration Ct load per human cell assessed (IFU/HLA copy) Geometric mean of concentration (IFU/HLA copy) Evaluation of a CRT as diagnostic for urogenital chlamydia in women at two study sites in Paramaribo, Suriname, from July 2009 to February 2010.
IFU; inclusion forming units.
HLA; human leucocyte antigen gene.
doi:10.1371/journal.pone.0032122.t003 February 2012 | Volume 7 | Issue 2 | e32122 In the CRT evaluation study performed in the Philippines, the commercially available products . Still, with a sensitivity of Ct prevalence was 6.3% in the low-risk group (women visiting an only 41.7%, this test performs under the minimally required obstetrics-gynaecology clinic) and 17.9 to 32% in the high-risk sensitivity of 63% required for a POC test to treat more infected group (female sex workers), which compares well with the individuals than the standard NAAT in a setting with low patient prevalences found in our study, 9.2% and 20.8% respectively.
return (,65%), . On the other hand, in situations where The sensitivity figures found in our study were comparable for transmission during treatment delay and low return for treatment low-risk and high-risk women, 42.0% and 39.4% respectively.
are considerable, even a POC test with a sensitivity below 63% Quite surprisingly, in the Philippines study a much lower could be beneficial in the prevention of ongoing STI transmission sensitivity was found in the high-risk group compared to the . A recent economic evaluation analysis using the same CRT low-risk group. The authors explain this finding as a result of the as we evaluated in this study, showed that in the UK using NAAT use of vaginal creams and other feminine hygiene products, which is more cost-effective. . In that evaluation, a sensitivity can interfere with the CRT. In our study, the sensitivity of CRT between 73% and 85% for the CRT was assumed.
was comparable for women who practiced any vaginal cleansing POC tests available for systemic infections like HIV and syphilis are highly sensitive since they are based on the detection of serum Although we consider the population recruited at Lobi antibodies [25,26]. Infections caused by organisms like Ct (but also Foundation a low risk group, with a prevalence of 9.2% this N. gonorrhoeae) are confined to mucosal tissue and normally invoke population would be considered high risk in many settings. Yet, little to no production of antibodies. Therefore, the development with a prevalence of 20.8% as found at the Dermatological of POC tests to diagnose mucosal Ct infections based on the Service, the difference in prevalence between the two study sites is detection of serum antibodies is, at least for now, not an option.
Improved POC tests for Ct need to detect bacterial antigens or The sensitivity of CRT is higher in samples with a high bacterial nucleic acids, even in cases with a low bacterial load. Promising load. The clinical relevance of organism load is still debated, but it steps have been made in the field of POC HIV-load NAAT using is suggested that infections with high organism loads are more nanotechnology . Along the same lines, a POC test for likely to lead to cervicitis or PID and are associated with multiple urogenital chlamydia with sufficient sensitivity could be developed.
patient-reported symptoms . However, the association with Until reliable and affordable diagnostics are available, algorithms patient-reported symptoms was only found with first-void urine for syndromic management can be used for low-resource settings, and endocervical samples and not with self-collected vaginal although the success of algorithms for vaginal discharge varies samples. In our study, where nurse-collected vaginal swabs were used, quantitative Ct loads were not significantly different for In conclusion, the evaluated CRT of Diagnostics for the Real asymptomatic women and women reporting one or multiplesymptoms such as vaginal discharge or dysuria.
World has no added value in the management of Ct infections due The NAAT platform is a latest generation highly sensitive to its low test performance. There is an urgent need for POC commercial diagnostic test for Ct . However no test is 100% diagnostics for the detection of urogenital chlamydia meeting the accurate and a positive bacterial Ct load signal was detected in two ASSURED criteria, including adequate sensitivity.
samples that were NAAT negative and CRT positive. One samplehad a Ct load of 62.9 IFU which might be explained by inhibition of high target load . The other sample had a very low load of The authors would like to express their gratitude to all nurses and 0.00261 IFU. Since the frequency of these discrepancies was laboratory technicians of the Dermatological Service and the Lobi extremely low, we do not consider that this finding significantly Foundation for data collection, and Susan T. Landry for editing the final A recent field study of the same CRT test but to detect ocular chlamydia infection (trachoma) found similar disappointingly low sensitivity (33.3%–67.9%) and specificity (92.4%–99.0%) .
Conceived and designed the experiments: JvdH LS SM AS HdV.
Most commercially available and clinically evaluated POC tests Performed the experiments: JvdH AG SM AS. Analyzed the data: JvdH for urogenital chlamydia show poor sensitivity results .
SM HdV. Contributed reagents/materials/analysis tools: LS AG SM AS Compared with the results found in our evaluation, the CRT of HdV. Wrote the paper: JvdH LS AG SM HdV.
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www.AJBlood.us /ISSN: 2160-1992/AJBR1105005 Review Article Mouse models as tools to understand and study BCR-ABL1 diseases Steffen Koschmieder, Mirle Schemionek Medizinische Klinik A, Universitätsklinikum Münster, Münster, Germany. Received May 16, 2011; accepted June 3, 2011; Epub June 7, 2011; published June 15, 2011 Abstract: Mouse models of human malignancy have greatly enhanced our