| 1. |
- Aarnio, Riina, 1971-, et al.
(författare)
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Comparison of vaginal self-sampling and cervical sampling by medical professionals for the detection of HPV and CIN2+ : a randomized study
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 148:12, s. 3051-3059
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Tidskriftsartikel (refereegranskat)abstract
- Primary screening with human papillomavirus (HPV) test is more effective in reducing cervical cancer incidence than cytology and it also offers the opportunity to self-sample. We conducted a randomized study to compare vaginal self-sampling with cervical sampling by medical professionals for HPV testing concerning prevalence of HPV and detection of cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in primary screening. In total, 11 951 women aged 30-60 years were randomized into two groups, 5961 for self-sampling (SS arm) and 5990 for sampling by medical professionals (SMP arm). Sampling was performed with a RoversViba-brush in the SS arm and a cytobrush in the SMP arm. All samples were applied to an indicating FTA elute card and analyzed for HPV using a clinically validated real-time PCR test (hpVIR). All HPV-positive women performed repeated sampling about 6 months later using the same procedure as used initially. All HPV-positive women in the second sampling were referred to colposcopy. The prevalence of HPV in the first test did not differ between the SS arm (6.8%, 167/2466) and the SMP arm (7.8%, 118/1519) (P = .255). The prevalence of CIN2+ per 1000 screened women was 17 (43/2466 × 1000) (95%CI 13-24) in the SS arm and 21 (32/1519 × 1000) (95%CI 15-30) in the SMP arm. For CIN3+, the prevalence per 1000 screened women was 14 (35/2466 × 1000) (95%CI 10-20) in the SS arm and 15 (23/1519 × 1000) (95%CI 10-23) in the SMP arm. In conclusion, self-sampling and sampling by medical professionals showed the same prevalence of HPV and detection rate of CIN2+ and CIN3+ in histology.
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| 2. |
- Aarnio, Riina, 1971-, et al.
(författare)
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Cost-effectiveness analysis of repeated self-sampling for HPV testing in primary cervical screening: a randomized study
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407 .- 1471-2407. ; 20:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundHuman papillomavirus (HPV) testing is recommended in primary cervical screening to improve cancer prevention. An advantage of HPV testing is that it can be performed on self-samples, which could increase population coverage and result in a more efficient strategy to identify women at risk of developing cervical cancer. Our objective was to assess whether repeated self-sampling for HPV testing is cost-effective in comparison with Pap smear cytology for detection of cervical intraepithelial neoplasia grade 2 or more (CIN2+) in increasing participation rate in primary cervical screening.MethodsA cost-effectiveness analysis (CEA) was performed on data from a previously published randomized clinical study including 36 390 women aged 30–49 years. Participants were randomized either to perform repeated self-sampling of vaginal fluid for HPV testing (n = 17 997, HPV self-sampling arm) or to midwife-collected Pap smears for cytological analysis (n = 18 393, Pap smear arm).ResultsSelf-sampling for HPV testing led to 1633 more screened women and 107 more histologically diagnosed CIN2+ at a lower cost vs. midwife-collected Pap smears (€ 228 642 vs. € 781 139). ConclusionsThis study projected that repeated self-sampling for HPV testing increased participation and detection of CIN2+ at a lower cost than midwife-collected Pap smears in primary cervical screening. Offering women a home-based self-sampling may therefore be a more cost-effective alternative than clinic-based screening.
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| 3. |
- Aarnio, Riina
(författare)
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Self-sampling for HPV testing in primary cervical screening : Including clinical and health economic aspects
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Persistent infection with high-risk human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. HPV testing has higher sensitivity for high-grade cervical intraepithelial neoplasia (CIN2+) than cytology, resulting in more effective screening. As HPV testing also offers an opportunity for self-sampling, it could serve as an even more effective and cost-effective method of cervical screening.First, we compared repeated self-sampling for HPV testing with Pap smear cytology in detection of CIN2+ in primary cervical screening for women aged 30–49 years (n=36 390). We found a more than twofold higher detection rate of CIN2+ and a fourfold higher detection rate of CIN2 with self-sampling compared with cytology. However, no difference was seen between the arms in the detection rate of CIN3+. It thus seems that CIN is detected at an earlier stage with self-sampling than with cytology, but the impact of this needs to be further explored.Second, as management of HPV-positive women with normal cytology results is a challenge, we wanted to evaluate the proportion of cases of histological CIN2+ in these women. In this prospective study we performed LEEP and found that 15% (6/40) of the women had undetected CIN2+. These findings can be used in counseling women about the risk of cervical cancer and helping clinicians in decisions on management.Third, we performed a cost-effectiveness analysis on the same study population as in Study I. Self-sampling for HPV testing resulted in a higher participation rate and more detected cases of CIN2+ at a lower cost and was regarded as more cost-effective than Pap smear cytology in cervical screening. These results can guide policy-makers when planning future screening programs.Fourth, we compared self-sampling with sampling by medical professionals for HPV testing in detection of CIN2+, using a combination of an FTA card as storage medium and a PCR-based HPV test (hpVIR) in women aged 30–60 years (n=11 951). No difference in the detection rates of histological CIN2+ was found between the arms.Taken together, self-sampling resulted in a higher participation rate than sampling by medical professionals in cervical screening and that triage with repeated self-sampling resulted in high compliance and detection rate of CIN2+. As repeated self-sampling for HPV testing was also cost-effective, it could serve as an attractive alternative in the development of future cervical screening programs. More research is needed on how to refine the management of HPV-positive women by self-sampling only.
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| 4. |
- Berggrund, Malin, 1989-
(författare)
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Identification and clinical implementation of biomarkers for cervical cancer
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction of organised screening programs and prophylactic vaccination against human papilloma virus (HPV) have successfully reduced the incidence of cervical cancer globally. In Sweden, the incidence has been reduced by about 50 % since the introduction of the national screening programme in the late 1960’s. Despite these efforts, cervical cancer is still a major cause of cancer deaths globally.In order to reduce cervical cancer, the screening program should have a high participation rate and be based on a sensitive and specific screening test. About 20 % of women in Sweden do not participate in the organised screening program, and during the last years we have also seen a rise in cervical cancer cases in Sweden among women who participate in the screening program. Thus, there is a need to develop improved screening strategies that result in a higher participation rate, and are based on tests that more precisely identify women with high risk of developing cervical cancer. This includes searching for novel biological markers (biomarkers) that can be used to more accurately identify women with a high risk of developing cervical cancer.By offering women self-sampling for HPV analysis through direct mailing of sample kits with a chemically treated paper card, the FTA card, we were able to increase the participation rate in the screening program. We also found that the use of repeated self-sampling for women that were HPV positive in the primary screening sample increased the number of women detected with higher risk of cervical cancer (Paper II). Self-sampling was shown to be non-inferior to assisted sampling by midwife (Paper III). Using this sample collection device, we further investigated the association between increased risk of cervical cancer and HPV viral load (Paper V) as well as the vaginal microbiota (Paper VI). We also showed that proteins in the vaginal fluid can be studied using self-sampling and the FTA card (Paper I). Lastly, we identified plasma proteins that are associated with cervical cancer and could represent future biomarkers (Paper IV).This thesis has provided novel aspects on the present screening strategy, explored opportunities to increase the participation rate as well as examined possible future biomarkers for screening of cervical cancer.
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| 5. |
- Berggrund, Malin, et al.
(författare)
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Temporal changes in the vaginal microbiota in self-samples and its association with persistent HPV16 infection and CIN2
- 2020
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Ingår i: Virology Journal. - : Springer Science and Business Media LLC. - 1743-422X. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe vaginal microbiota has been reported to be associated with HPV infection and cervical cancer. This study was performed to compare the vaginal microbiota at two timepoints in women performing self-sampling and had a persistent or transient HPV16 infection. The women were tested for 12 high-risk HPV (hrHPV) types but only women with single type (HPV16) were included to reduce confounding variables.MethodsIn total 96 women were included in this study. Of these, 26 were single positive for HPV16 in the baseline test and HPV negative in the follow-up test and 38 were single positive for HPV16 in both tests and diagnosed with CIN2+ in histology. In addition, 32 women that were negative for all 12 HPV tested were included. The samples of vaginal fluid were analyzed with the Ion 16S™ Metagenomics Kit and Ion 16S™ metagenomics module within the Ion Reporter™ software.ResultsK-means clustering resulted in two Lactobacillus-dominated groups, one with Lactobacillus sp. and the other specifically with Lactobacillus iners. The two remaining clusters were dominated by a mixed non-Lactobacillus microbiota. HPV negative women had lower prevalence (28%) of the non-Lactobacill dominant cluster in the baseline test, as compared to women with HPV16 infection (42%) (p value = 0.0173). Transition between clusters were more frequent in women with persistent HPV16 infection (34%) as compared in women who cleared the HPV16 infection (19%) (p value = 0.036).ConclusionsThe vaginal microbiota showed a higher rate of transitioning between bacterial profiles in women with persistent HPV16 infection as compared to women with transient infection. This indicate an instability in the microenvironment in women with persistent HPV infection and development of CIN2+.
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| 6. |
- Dumanski, Jan P., et al.
(författare)
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Immune cells lacking Y chromosome show dysregulation of autosomal gene expression
- 2021
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 78:8, s. 4019-4033
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
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| 7. |
- Fatima, Nazeefa, et al.
(författare)
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Evaluation of Single-Molecule Sequencing Technologies for Structural Variant Detection in Two Swedish Human Genomes
- 2020
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Ingår i: Genes. - : MDPI AG. - 2073-4425 .- 2073-4425. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Long-read single molecule sequencing is increasingly used in human genomics research, as it allows to accurately detect large-scale DNA rearrangements such as structural variations (SVs) at high resolution. However, few studies have evaluated the performance of different single molecule sequencing platforms for SV detection in human samples. Here we performed Oxford Nanopore Technologies (ONT) whole-genome sequencing of two Swedish human samples (average 32x coverage) and compared the results to previously generated Pacific Biosciences (PacBio) data for the same individuals (average 66x coverage). Our analysis inferred an average of 17k and 23k SVs from the ONT and PacBio data, respectively, with a majority of them overlapping with an available multi-platform SV dataset. When comparing the SV calls in the two Swedish individuals, we find a higher concordance between ONT and PacBio SVs detected in the same individual as compared to SVs detected by the same technology in different individuals. Downsampling of PacBio reads, performed to obtain similar coverage levels for all datasets, resulted in 17k SVs per individual and improved overlap with the ONT SVs. Our results suggest that ONT and PacBio have a similar performance for SV detection in human whole genome sequencing data, and that both technologies are feasible for population-scale studies.
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| 8. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 9. |
- Gyllensten, Ulf B., et al.
(författare)
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Preoperative Fasting and General Anaesthesia Alter the Plasma Proteome
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Blood plasma collected at time of surgery is an excellent source of patient material for investigations into disease aetiology and for the discovery of novel biomarkers. Previous studies on limited sets of proteins and patients have indicated that pre-operative fasting and anaesthesia can affect protein levels, but this has not been investigated on a larger scale. These effects could produce erroneous results in case-control studies if samples are not carefully matched. Methods: The proximity extension assay (PEA) was used to characterize 983 unique proteins in a total of 327 patients diagnosed with ovarian cancer and 50 age-matched healthy women. The samples were collected either at time of initial diagnosis or before surgery under general anaesthesia. Results: 421 of the investigated proteins (42.8%) showed statistically significant differences in plasma abundance levels comparing samples collected at time of diagnosis or just before surgery under anaesthesia. Conclusions: The abundance levels of the plasma proteome in samples collected before incision, i.e., after short-time fasting and under general anaesthesia differs greatly from levels in samples from awake patients. This emphasizes the need for careful matching of the pre-analytical conditions of samples collected from controls to cases at time of surgery in the discovery as well as clinical use of protein biomarkers.
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| 10. |
- Halvorsen, Matthew, et al.
(författare)
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Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1, s. 1842-
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Tidskriftsartikel (refereegranskat)abstract
- Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.
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