| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- Höijer, Ida, et al.
(författare)
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Amplification-free long-read sequencing reveals unforeseen CRISPR-Cas9 off-target activity
- 2020
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: One ongoing concern about CRISPR-Cas9 genome editing is that unspecific guide RNA (gRNA) binding may induce off-target mutations. However, accurate prediction of CRISPR-Cas9 off-target activity is challenging. Here, we present SMRT-OTS and Nano-OTS, two novel, amplification-free, long-read sequencing protocols for detection of gRNA-driven digestion of genomic DNA by Cas9 in vitro.RESULTS: The methods are assessed using the human cell line HEK293, re-sequenced at 18x coverage using highly accurate HiFi SMRT reads. SMRT-OTS and Nano-OTS are first applied to three different gRNAs targeting HEK293 genomic DNA, resulting in a set of 55 high-confidence gRNA cleavage sites identified by both methods. Twenty-five of these sites are not reported by off-target prediction software, either because they contain four or more single nucleotide mismatches or insertion/deletion mismatches, as compared with the human reference. Additional experiments reveal that 85% of Cas9 cleavage sites are also found by other in vitro-based methods and that on- and off-target sites are detectable in gene bodies where short-reads fail to uniquely align. Even though SMRT-OTS and Nano-OTS identify several sites with previously validated off-target editing activity in cells, our own CRISPR-Cas9 editing experiments in human fibroblasts do not give rise to detectable off-target mutations at the in vitro-predicted sites. However, indel and structural variation events are enriched at the on-target sites.CONCLUSIONS: Amplification-free long-read sequencing reveals Cas9 cleavage sites in vitro that would have been difficult to predict using computational tools, including in dark genomic regions inaccessible by short-read sequencing.
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| 10. |
- Nordin, Jessika, et al.
(författare)
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SweHLA : the high confidence HLA typing bio-resource drawn from 1000 Swedish genomes
- 2020
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 28:5, s. 627-635
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Tidskriftsartikel (refereegranskat)abstract
- There is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of Sanger sequenced lab typing. Here we aimed to combine results from available software programs, minimizing the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1000 Swedish genomes, and a framework for future HLA interrogation. HLA 2nd-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A, HLA-B, HLA-C; class II: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1). A high confidence population set (SweHLA) was determined using an n−1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and individual programs benchmarked to SweHLA. Per gene, 875 to 988 of the 1000 samples were genotyped in SweHLA; 920 samples had at least seven loci called. While a small fraction of reference alleles were common to all software (class I = 1.9% and class II = 4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations (>0.83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency >2) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software solutions. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to individual HLA software biases.
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