***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Cytology is a widely used method of triaging women who test positive for human papillomavirus ( HPV ) . However , self- sample d specimens , which can substantially increase participation in screening programmes , are not suitable for accurate cytological assessment . We investigated whether direct DNA methylation-based molecular triage on self- sample d cervicovaginal specimens was non-inferior to cytology triage on additional physician-collected cervical sample s in the detection of cervical intraepithelial neoplasia grade 2 ( CIN2 ) or worse in women who did not attend cervical screening programmes . METHODS In this r and omised controlled non-inferiority trial , we invited women ( aged 33 - 63 years ) registered as non-attendees of cervical screening in the Netherl and s in 2007 to su bmi t a self-collected cervicovaginal sample for HPV testing .  Using a computer-generated sequence , we r and omly allocated women who tested positive for high-risk hrHPV on a self- sample  to either triage by cytology on an additional physician-taken smear or direct triage on the self- sample by methylation analysis of MAL and miR-124 - 2 genes ( 1:1 ; stratified by age and region , with block sizes by age group ) . Triage-positive women in either group were referred for colposcopy . The primary endpoint was detection of CIN2 or worse , analysed by intention to treat . The non-inferiority margin was 0·80 . This study is registered in the Primary Trial Register of the Netherl and s , number NTR6026 . FINDINGS We invited 46,001 women to participate , 12,819 of whom returned self- sample d material ; 1038 sample s tested positive for high-risk HPV . Between Nov 1 , 2010 , and Dec 31 , 2011 , after exclusion of women who were ineligible , we enrolled and r and omly allocated 515 women to methylation triage and 509 to cytology triage . The detection of CIN2 or worse with methylation triage was non-inferior to that with cytology triage ( 90 [ 17 % ] of 515 women vs 75 [ 15 % ] of 509 women ; relative risk 1·19 , 95 % CI 0·90 - 1·57 ) . Referral for colposcopy was more common in the molecular group ( 284 [ 55 % ] women ) than in the cytology group ( 149 [ 29 % ] women ; p<0·0001 ) . Mean time to CIN2 or worse diagnosis was shorter in the molecular triage group ( 96 days , range 44 - 101 ) than in the cytology triage group ( 158 days , 71 - 222 ; p=0·00084 ) . INTERPRETATION DNA methylation analysis of MAL and miR-124 - 2 genes on HPV-test-positive self- sample s is non-inferior to cytology triage in the detection of CIN2 or worse , opening the way to full molecular screening . FUNDING Midden-West and Oost Screening Organisations and Stichting Achmea Gezondheidszorg OBJECTIVE Our previous work revealed that host genes ZNF582 , PTPRR , PAX1 , and SOX1 are highly methylated in cervical intraepithelial neoplasias grade 3 or worse ( CIN3(+ ) ) . In this study , we used a st and ardized testing assay to evaluate the clinical efficacy of these biomarkers in the triage of cytological diagnoses of low- grade squamous intraepithelial lesions ( LSILs ) , and compared the performance with human papillomavirus ( HPV ) testing . METHODS This 2-year multicenter prospect i ve study examined a population of 230 women from 12 medical centers who were diagnosed with LSILs on cervical cytology .  Cervical scrapings were obtained prior to a colposcopy-directed biopsy for quantitative methylation analysis of ZNF582 , PTPRR , PAX1 , and SOX1 , and HPV testing . Using logistic regression and receiver operating characteristic curve analyses , the abilities of methylated genes and HPV to predict CIN3(+ ) were assessed . RESULTS Fifteen ( 6.5 % ) of the 230 women with a cytological diagnosis of LSIL were confirmed to have CIN3(+ ) after a colposcopy-directed biopsy . Among the 4 methylated genes , ZNF582 was found to be the best biomarker for detecting CIN3(+ ) . The sensitivities for methylated ZNF582 and HPV testing were 73 % and 80 % , and the specificities were 71 % and 28 % , respectively . The odds ratio for predicting CIN3(+ ) using methylated ZNF582 was 6.8 ( 95 % confidence interval ( CI ) 2.1 - 22.1 ) , which was much better than HPV testing ( OR=1.6 , 95 % CI 0.4 - 5.8 ) . CONCLUSION This is the first study to show that ZNF582 methylation analysis of cervical swabs may be a promising choice in the positive triage of cytological diagnoses of LSILs An accurate biomarker for the follow-up of women positive for human papillomavirus type 16 ( HPV16 ) DNA may improve the efficiency of cervical cancer prevention . Previously , we analyzed all 113 HPV16 CpGs in cervical cytology sample s and discovered differential methylation at different stages of premalignancy . In the current study , we identified a methylation biomarker consisting of a panel of 12 HPV16 CpG sites in the E5 , L2 , and L1 open reading frames , and tested whether it fulfilled three necessary conditions of a prospect i ve biomarker . A total of 33 cytology sample s from North American and West African women with all grade s of cervical intraepithelial neoplasia ( CIN ) and invasive cervical cancer ( ICC ) were analyzed by using DNA bisulfite sequencing . The results showed ( i ) a highly significant trend for increasing HPV16 biomarker methylation with increasing histologic severity ( P < 0.0001 ) , ( ii ) 100 % sensitivity for ICC over a wide range of methylation cutoff scores ; 80 % detection of CIN3 at cutoff scores up to 39 % methylation , and ( iii ) substantially lower detection of CIN2 , from 0 % to 71 % , depending on the cutoff score . Our results support the prognostic potential of the HPV16 methylation biomarker for the triage to colposcopy of women with HPV16-positive screening tests and , eventually , for the management of women with HPV16-positive CIN2 . Cancer Prev Res ; 7(5 ) ; 526–33 . © 2014 AACR DNA methylation changes in human papillomavirus type 16 ( HPV16 ) DNA are common and might be important for identifying women at increased risk of cervical cancer . Using recently published data from Costa Rica we developed a classification score to differentiate women with cervical intraepithelial neoplasia grade 2 or 3 ( CIN2/3 ) from those with no evident high- grade lesions . Here , we aim to investigate the performance of the score using data from the UK . Exfoliated cervical cells at baseline and 6-months follow-up were analyzed in 84 women selected from a r and omized clinical trial of women undergoing surveillance for low- grade cytology . Selection of women for the methylation study was based on detectable HPV16 in the baseline sample . Purified DNA was bisulfite converted , amplified and pyrosequenced at selected CpG sites in the viral genome ( URR , E6 , L1 and L2 ) , with blinding of laboratory personnel to the clinical data . The primary measure was a predefined score combining the mean methylation in L1 and any methylation in L2 . At the second follow-up visit , 73/84 ( 87 % ) women were HPV16 positive and of these 25 had a histopathological diagnosis of CIN2/3 . The score was significantly associated with CIN2/3 ( area under curve = 0.74 , p = 0.002 ) . For a cutoff with 92 % sensitivity , colposcopy could have been avoided in 40 % ( 95 % CI 27–54 % ) of HPV16 positive women without CIN2/3 ; positive predictive value was 44 % ( 32–58 % ) and negative predictive value was 90 % ( 71–97 % ) . We conclude that quantitative DNA methylation assays could help to improve triage among HPV16 positive women Objective : Cervical cancer is the leading cause of cancer-related death in women in South Africa . This study evaluates DNA methylation levels in cervical (pre)cancer and aims to assess the value of high-risk human papillomavirus ( hrHPV ) testing and methylation analysis , alone or in combination , on physician-taken cervical scrapes to detect cervical cancer , and cervical intraepithelial neoplasia grade 3 ( CIN3 ) in an HIV-infected South African population . Design : Prospect i ve observational multicentre cohort study . Methods : Women from a cohort of women living with HIV ( n = 355 ) and a referral cohort ( n = 109 , 60 % HIV seropositive ) were included .  Cervical scrapes were collected for hrHPV testing and methylation analysis of cell adhesion molecule 1 , T-lymphocyte maturation-associated protein , and microRNA124 - 2 genes . Histologic endpoints were available for all participants . Performance for detection of CIN3 or worse ( CIN3 + ) was determined in the cohort of women living with HIV and different testing strategies were compared . Results : HrHPV and methylation positivity rates increased with severity of cervical disease in the two study cohorts , each reaching 100 % in sample s of women with carcinoma . HrHPV testing showed a sensitivity for CIN3 + of 83.6 % , at a specificity of 67.7 % . Methylation analysis showed a comparable CIN3 + sensitivity of 85.2 % , but a significantly lower specificity of 49.6 % . HrHPV testing with reflex methylation analysis showed a CIN3 + sensitivity of 73.8 % , at a specificity of 81.5 % . Conclusion : In this HIV-infected South African population , stratifying hrHPV-positive women with reflex methylation analysis detects all cervical carcinomas and yields an acceptable sensitivity and specificity for CIN3 + Recently , DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high- grade cervical intraepithelial neoplasia and cervical cancer ( ≥ CIN3 ) in high-risk HPV (hrHPV)-positive women . Here , we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping , separately and in combination , for ≥ CIN3 detection in hrHPV-positive women participating in a prospect i ve observational multi-center cohort study . The study population comprised hrHPV-positive women aged 18 - 66 years , visiting a gynecological outpatient clinic . From these women , cervical scrapes and colposcopy-directed biopsies ( for histological confirmation ) were obtained . Cervical scrapes were analyzed for FAM19A4 gene promoter methylation , cytology and HPV16/18 genotyping . Methylation analysis was performed by quantitative methylation-specific PCR ( qMSP ) . Sensitivities and specificities for ≥ CIN3 were compared between tests . Stratified analyses were performed for variables that potentially influence marker performance . Of all 508 hrHPV-positive women , the sensitivities for ≥ CIN3 of cytology  , FAM19A4 methylation analysis , and cytology combined with HPV16/18 genotyping were 85.6 , 75.6 and 92.2 % , respectively , with corresponding specificities of 49.8 , 71.1 and 29.4 % , respectively . Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age ( p ≤ 0.001 each ) . In women ≥ 30 years ( n = 287 ) , ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3 % ( 95%CI : 80.2 - 96.5 ) which was noninferior to that of cytology [ 85.5 % ( 95%CI : 76.0 - 94.0 ) ] , at a significantly higher specificity [ 62.1 % ( 95%CI : 55.8 - 68.4 ) compared to 47.6 % ( 95%CI : 41.1 - 54.1 ) ] . In conclusion , among hrHPV-positive women from an outpatient population aged ≥ 30 years , methylation analysis of FAM19A4 
    Output:
    
Conclusion DNA methylation is significantly higher in CIN2 + and CIN3 + compared to ≤CIN1 .
As triage test , DNA methylation has higher specificity than cytology ASCUS+ and higher sensitivity than HPV16/18 genotyping