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Background: We report our experience of selecting tag SNPs in 35 genes involved in iron metabolism in a cohort study seeking to discover genetic modifiers of hereditary hemochromatosis. Methods: We combined our own and publicly available resequencing data with HapMap to maximise our coverage to select 384 SNPs in candidate genes suitable for typing on the Illumina platform. Results: Validation/ design scores above 0.6 were not strongly correlated with SNP performance as estimated by Gentrain score. We contrasted results from two tag SNP selection algorithms, LDselect and Tagger. Varying r(2) from 0.5 to 1.0 produced a near linear correlation with the number of tag SNPs required. We examined the pattern of linkage disequilibrium of three levels of resequencing coverage for the transferrin gene and found HapMap phase 1 tag SNPs capture 45% of the >= 3% MAF SNPs found in SeattleSNPs where there is nearly complete resequencing. Resequencing can reveal adjacent SNPs ( within 60 bp) which may affect assay performance. We report the number of SNPs present within the region of six of our larger candidate genes, for different versions of stock genotyping assays. Conclusion: A candidate gene approach should seek to maximise coverage, and this can be improved by adding to HapMap data any available sequencing data. Tag SNP software must be fast and flexible to data changes, since tag SNP selection involves iteration as investigators seek to satisfy the competing demands of coverage within and between populations, and typability on the technology platform chosen.

Keywords: Population health; Population policy; Registries; Public health; Health promotion; Early detection of cancer; Mass screening EN Population health Population policy Registries Public health Health promotion Early detection of cancer Mass screening 94 98 5 08/08/23 20230807 NES 230807 A national digital infrastructure designed to support health care providers delivering bowel and cervical cancer screening Registers are a key element of organised population-based cancer screening programs. Unlike cancer registers, which focus on collection and reporting of cancer diagnoses, cancer screening registers are digital platforms that support all aspects of the operations of screening programs by inviting, reminding and following up participants for screening. Legislation enabling the NCSR to operate as an opt-out register (the I National Cancer Screening Register Act 2016 i ) was passed in 2016 and permitted the NCSR to receive results for relevant cancer screening and diagnostic tests. [Extracted from the article]

The prevalence of iron-overload-related disease for C282Y homozygotes is examined. Findings reveal the development of iron-overload-related disease in a substantial proportion of men due to elevated levels of serum ferritin and transferrin saturation.

Background Using primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplastic lesions and invasive cancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) compared to cytology, but no evaluation has been conducted in a population previously offered HPV vaccination. We aimed to assess colposcopy referral and CIN2+ detection rates for HPV-screened versus cytology-screened women in Australia's HPV-vaccinated population (by 2014, resident women [less than or equal to]33 years had been age-eligible for HPV vaccination, with 3-dose uptake across age cohorts being about 50%-77%). Methods and findings Compass is an open-label randomised trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening. In the first phase, consenting women aged 25-64 years presenting for routine screening at 47 primary practices in Victoria, Australia, provided a cervical sample and were randomised at a central laboratory at a 1:2:2 allocation to (i) image-read LBC screening with HPV triage of low-grade cytology ('LBC screening'), (ii) HPV screening with those HPV16/18 positive referred to colposcopy and with LBC triage for other oncogenic (OHR) types ('HPV+LBC triage'), or (iii) HPV screening with those HPV16/18 positive referred to colposcopy and with dual-stained cytology triage for OHR types ('HPV+DS triage'). A total of 5,006 eligible women were recruited from 29 October 2013 to 7 November 2014 (recruitment rate 58%); of these, 22% were in the group age-eligible for vaccination. Data on 4,995 participants were analysed after 11 withdrawals; 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. No serious trial-related adverse events were reported. The main outcomes were colposcopy referral and detected CIN2+ rates at baseline screening, assessed on an intention-to-treat basis after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes (dataset closed 31 August 2016). Analysis was adjusted for whether women had been age-eligible for HPV vaccination or not. For the LBC-screened group, the overall referral and detected CIN2+ rates were 27/995 (2.7% [95% CI 1.8%-3.9%]) and 1/995 (0.1% [95% CI 0.0%-0.6%]), respectively; for HPV+LBC triage, these were 75/1,992 (3.8% [95% CI 3.0%-4.7%]) and 20/1,992 (1.0% [95% CI 0.6%-1.5%]); and for HPV+DS triage, these were 79/2,008 (3.9% [95% CI 3.1%-4.9%]) and 24/2,008 (1.2% [95% CI 0.8%-1.6%]) (p = 0.09 for difference in referral rate in LBC versus all HPV-screened women; p = 0.003 for difference in CIN2+ detection rate in LBC versus all HPV-screened women, with p = 0.62 between HPV screening groups). Limitations include that the study population involved a relatively low risk group in a previously well-screened and treated population, that individual women's vaccination status was unknown, and that long-term follow-up data on disease detection in screen-negative women are not yet available. Conclusions In this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. It had been predicted that increased disease detection might be associated with a transient increase in colposcopy referral rates in the first round of HPV screening, possibly dampened by HPV vaccine effect; in this study, although the point estimates for referral rates in women in each HPV-screened group were 41%-44% higher than in cytology-screened women, the difference in referral rate between cytology- and HPV-screened women was not significant. These findings provide initial support for the implementation of primary HPV screening in vaccinated populations. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001207707, Author(s): Karen Canfell 1,2,3,*, Michael Caruana 1, Val Gebski 4, Jessica Darlington-Brown 1, Stella Heley 5, Julia Brotherton 5,6, Dorota Gertig 6, Chloe J. Jennett 1, Annabelle Farnsworth 2,7, Jeffrey [...]

Author(s): Douglas F. Easton (corresponding author) [1]; Karen A. Pooley [2]; Alison M. Dunning [2]; Paul D. P. Pharoah [2]; Deborah Thompson [1]; Dennis G. Ballinger [3]; Jeffery P. Struewing [...]

Hereditary haemochromatosis (HH) is an inherited disorder of iron absorption. It meets several of the key public health principles for population-based screening and is considered to be a test-case for public health genetics. However, there has been relatively little debate in the public health or wider community regarding the merits of population-based genetic screening for HH. Genetic susceptibility to HH occurs in about 1:200 people and although mortality is low (age-standardised rate 2.75/million), there are potentially serious clinical manifestations of iron overload. Regular venesection is a simple and effective treatment for early stage iron overload. DNA-based testing is available and iron overload may be identified using serum transferrin saturation and ferritin tests. However, there are important gaps in knowledge relevant to screening for HH. The limited data on penetrance of HFE genotypes, and thus the uncertain probability that genetically susceptible individuals will develop clinically significant disease, is a major impediment to population-based genetic screening. Clinical evidence supports treating early-stage disease but no randomised controlled trials of the effectiveness of screening in reducing the burden of disease have been conducted. In addition, the natural history of early stages of HH and factors that may modify progression are unclear. Two international consensus panels on HH concluded that there is insufficient evidence for population-based screening at present. We present recommendations to advance the debate on screening for HH in Australia.

Objectives. The purpose of this study was to describe the establishment of a national surveillance system for newly acquired human immunodeficiency virus (HIV) infection and present the first 3 years' results. Methods. All new cases of diagnosed HIV infection were reported to the national HIV surveillance center through state and territory health authorities. Information sought on each case included evidence of whether the infection had been newly acquired, defined by the diagnosis of HIV seroconversion illness or by the report of a negative or indeterminate HIV antibody test result occurring within the 12 months prior to diagnosis of infection. Results. Of 3602 reported cases of HIV infection in adults and adolescents newly diagnosed in Australia between 1991 and 1993,11.4% were identified as newly acquired. The majority (85%) of cases of newly diagnosed HIV infection occurred among men who reported homosexual contact, and 15% of these cases were identified as newly acquired. Average age at diagnosis was 31 years for cases of newly acquired infection and 34 years for other cases. Conclusions. Surveillance for newly acquired HIV infection has been established at a national level in Australia and provides valuable information for planning primary HIV prevention programs. (Am J Public Health. 1994;84:1923-1928), National surveillance data on newly acquired HIV infections in Australia appear to indicate a significant increase in the number of cases contracted between 1991 and 1993. Each health authority in Australia is required to report cases of HIV infection to the national HIV surveillance center. Data suggest there were 410 (11.4%) newly acquired HIV cases among a total of 3602 new infections reported between 1991 and 1993. Most of the cases involved men who were an average of 31 years of age and had homosexual contacts. The marked increase in new infections, from 131 in 1991 to 327 in 1993, may be due to higher reporting accuracy or reflect actual prevalence changes. The relatively low incidence of HIV infection linked to heterosexual activity and intravenous drug use is consistent with previous prevalence data in Australia.

Abstract Background The National Cervical Screening Program in Australia currently recommends that women aged 18–69 years are screened with conventional cytology every 2 years. Publicly funded HPV vaccination was introduced in 2007, and partly as a consequence, a renewal of the screening program that includes a review of screening recommendations has recently been announced. This study aimed to provide a baseline for such a review by quantifying screening program resource utilisation and costs in 2010. Methods A detailed model of current cervical screening practice in Australia was constructed and we used data from the Victorian Cervical Cytology Registry to model age-specific compliance with screening and follow-up. We applied model-derived rate estimates to the 2010 Australian female population to calculate costs and numbers of colposcopies, biopsies, treatments for precancer and cervical cancers in that year, assuming that the numbers of these procedures were not yet substantially impacted by vaccination. Results The total cost of the screening program in 2010 (excluding administrative program overheads) was estimated to be A$194.8M. We estimated that a total of 1.7 million primary screening smears costing $96.7M were conducted, a further 188,900 smears costing $10.9M were conducted to follow-up low grade abnormalities, 70,900 colposcopy and 34,100 histological evaluations together costing $21.2M were conducted, and about 18,900 treatments for precancerous lesions were performed (including retreatments), associated with a cost of $45.5M for treatment and post-treatment follow-up. We also estimated that $20.5M was spent on work-up and treatment for approximately 761 women diagnosed with invasive cervical cancer. Overall, an estimated $23 was spent in 2010 for each adult woman in Australia on cervical screening program-related activities. Conclusions Approximately half of the total cost of the screening program is spent on delivery of primary screening tests; but the introduction of HPV vaccination, new technologies, increasing the interval and changing the age range of screening is expected to have a substantial impact on this expenditure, as well as having some impact on follow-up and management costs. These estimates provide a benchmark for future assessment of the impact of changes to screening program recommendations to the costs of cervical screening in Australia.

Abstract Background We report our experience of selecting tag SNPs in 35 genes involved in iron metabolism in a cohort study seeking to discover genetic modifiers of hereditary hemochromatosis. Methods We combined our own and publicly available resequencing data with HapMap to maximise our coverage to select 384 SNPs in candidate genes suitable for typing on the Illumina platform. Results Validation/design scores above 0.6 were not strongly correlated with SNP performance as estimated by Gentrain score. We contrasted results from two tag SNP selection algorithms, LDselect and Tagger. Varying r2 from 0.5 to 1.0 produced a near linear correlation with the number of tag SNPs required. We examined the pattern of linkage disequilibrium of three levels of resequencing coverage for the transferrin gene and found HapMap phase 1 tag SNPs capture 45% of the ≥ 3% MAF SNPs found in SeattleSNPs where there is nearly complete resequencing. Resequencing can reveal adjacent SNPs (within 60 bp) which may affect assay performance. We report the number of SNPs present within the region of six of our larger candidate genes, for different versions of stock genotyping assays. Conclusion A candidate gene approach should seek to maximise coverage, and this can be improved by adding to HapMap data any available sequencing data. Tag SNP software must be fast and flexible to data changes, since tag SNP selection involves iteration as investigators seek to satisfy the competing demands of coverage within and between populations, and typability on the technology platform chosen.

Background: Adenocarcinoma in situ of cervix is increasingly managed by local excision rather than hysterectomy and this study will ascertain if conservative management by excision alone is adequate. Aims: To evaluate the long‐term outcomes of conservative management of adenocarcinoma in situ of cervix, particularly in relation to excisional margin status. Materials and Methods: Retrospective analysis of women diagnosed with adenocarcinoma in situ and their management between 1992 and 2010 retrieved from the Victorian Cervical Cytology Registry, Australia. Failure of conservative treatment is defined by histologically proven adenocarcinoma in situ or adenocarcinoma at follow‐up after negative excisional margins. Results: adenocarcinoma in situ of the cervix was managed primarily with cold knife cone biopsy or loop electrosurgical excision of the cervix. Most excisions were in one piece (83.4%) with average depth of 16.1 mm and 21.9% had involved excisional margins. Women with adenocarcinoma in situ on any excisional margin were more likely to have residual or recurrent disease (28.7%) compared with negative excisional margins (4.3%). Residual adenocarcinoma in situ was twice as common if adenocarcinoma in situ was present at endocervical (29.6%) and stromal (23.1%) margins compared with an ectocervical margin (13.6%). Cancer incidence at follow‐up was 2.3% for women with positive excisional margins compared to 1.3% with negative margins. Conclusions: Women with adenocarcinoma in situ of cervix can be managed with local excisional procedures, best in single pieces to provide the important information on excisional margins. Adenocarcinoma in situ at endocervical and stromal excisional margins needs re‐excision or where appropriate, hysterectomy, while negative excisional margins have a low rate of recurrence and can be followed up with test of cure. [ABSTRACT FROM AUTHOR]