| 1. |
- Baltzer, Nicholas, et al.
(författare)
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Risk stratification in cervical cancer screening by complete screening history : Applying bioinformatics to a general screening population
- 2017
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 141:1, s. 200-209
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Tidskriftsartikel (refereegranskat)abstract
- Women screened for cervical cancer in Sweden are currently treated under a one-size-fits-all programme, which has been successful in reducing the incidence of cervical cancer but does not use all of the participants' available medical information. This study aimed to use women's complete cervical screening histories to identify diagnostic patterns that may indicate an increased risk of developing cervical cancer. A nationwide case-control study was performed where cervical cancer screening data from 125,476 women with a maximum follow-up of 10 years were evaluated for patterns of SNOMED diagnoses. The cancer development risk was estimated for a number of different screening history patterns and expressed as Odds Ratios (OR), with a history of 4 benign cervical tests as reference, using logistic regression. The overall performance of the model was moderate (64% accuracy, 71% area under curve) with 61-62% of the study population showing no specific patterns associated with risk. However, predictions for high-risk groups as defined by screening history patterns were highly discriminatory with ORs ranging from 8 to 36. The model for computing risk performed consistently across different screening history lengths, and several patterns predicted cancer outcomes. The results show the presence of risk-increasing and risk-decreasing factors in the screening history. Thus it is feasible to identify subgroups based on their complete screening histories. Several high-risk subgroups identified might benefit from an increased screening density. Some low-risk subgroups identified could likely have a moderately reduced screening density without additional risk.
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| 2. |
- Baltzer, Nicholas, et al.
(författare)
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Stratifying Cervical Cancer Risk With Registry Data
- 2018
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Ingår i: 2018 IEEE 14th International Conference on e-Science (e-Science 2018). - : IEEE. - 9781538691564 ; , s. 288-289
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Konferensbidrag (refereegranskat)abstract
- The cervical cancer screening programmes in Sweden and Norway have successfully reduced the frequency of cervical cancer incidence but have not implemented any form of evaluation for screening needs. This means that the screening frequency for individuals can he suboptimal, increasing either the cost of the programme or the risk of missing an early stage cancer development. We developed a framework for assessing an individual's risk of cervical cancer based on their available screening history and computing a primary risk factor called CRS from a data-driven separation model together with multiple derived attributes. The results show that this approach is highly practical, validates against multiple established trends, and can he effective in personalizing the screening needs for individuals.
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| 3. |
- Cavalli, Marco, et al.
(författare)
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Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.
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| 4. |
- Diamanti, Klev, et al.
(författare)
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Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 9653-
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.
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| 5. |
- Umer, Husen Muhammad
(författare)
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Computational Modelling of Gene Regulation in Cancer : Coding the noncoding genome
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Technological advancements have enabled quantification of processes within and around us. The information stored within our body converts into petabytes of data. Processing and learning from such data requires comprehensive computational programs and software systems. We developed software programs to systematically investigate the process of gene regulation in the human genome. Gene regulation is a complex process where several genomic elements control expression of a gene through recruiting many transcription factor (TF) proteins. The TFs recognize specific DNA sequences known as motifs. DNA mutations in regulatory elements and particularly in TF motifs may cause gene deregulation. Therefore, defining the landscape of regulatory elements and their roles in cancer and complex diseases is of major importance.We developed an algorithm (tfNet) to identify regulatory elements based on transcription factor binding sites. tfNet identified nearly 144,000 regulatory elements in five human cell lines. Investigating the elements we identified TF interaction networks and enrichment of many GWAS SNPs. We also defined the regulatory landscape for other conditions and species. Next, we investigated the role of regulatory elements in cancer. Cancer is initiated and developed by genetic aberrations in the genome. Genetic changes that are present in a cancer genome are obtained through whole genome sequencing technologies. We analyzed somatic mutations that had been detected in 326 whole genomes of liver cancer patients. Our results indicated 907 candidate mutations affecting TF motifs. Genome wide alignment of the mutated motifs revealed a significant enrichment of mutations in a highly conserved position of the CTCF motif. Gene expression analysis exhibited disruption of topologically associated domains in the mutated samples. We also confirmed the mutational pattern in pancreatic, gastric and esophagus cancers. Finally, enrichment of cancer associated gene sets and pathways suggested great role of noncoding mutations in cancer.To systematically analyze DNA mutations in TF motifs, we developed an online database system (funMotifs). Publicly available datasets were collected for thousands experiments. The datasets were integrated using a logistic regression model. Functionality annotations and scores for motifs of 519 TFs were derived. The database allows for identification of variants affecting functional motifs in a selected tissue type. Finally, a comprehensive analysis was performed to identify mutations overlapping functional TF motifs in 37 cancer types. Somatic mutations from a pan-cancer cohort of 2,515 cancer whole genomes were investigated. A significant enrichment of mutations in the CpG site of the CEBPB motif was identified. Overall, 10,806 mutated regulatory elements were identified including 406 highly recurrent ones. Genes associated to the mutated elements were highly enriched for cancer-related pathways. Our analyses provide further insights onto the role of regulatory elements and their impacts on cancer development.
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| 6. |
- Baltzer, Nicholas
(författare)
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Predictive Healthcare : Cervical Cancer Screening Risk Stratification and Genetic Disease Markers
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The use of Machine Learning is rapidly expanding into previously uncharted waters. In the medicine fields there are vast troves of data available from hospitals, biobanks and registries that now are being explored due to the tremendous advancement in computer science and its related hardware. The progress in genomic extraction and analysis has made it possible for any individual to know their own genetic code. Genetic testing has become affordable and can be used as a tool in treatment, discovery, and prognosis of individuals in a wide variety of healthcare settings. This thesis addresses three different approaches to-wards predictive healthcare and disease exploration; first, the exploita-tion of diagnostic data in Nordic screening programmes for the purpose of identifying individuals at high risk of developing cervical cancer so that their screening schedules can be intensified in search of new dis-ease developments. Second, the search for genomic markers that can be used either as additions to diagnostic data for risk predictions or as can-didates for further functional analysis. Third, the development of a Ma-chine Learning pipeline called ||-ROSETTA that can effectively process large datasets in the search for common patterns. Together, this provides a functional approach to predictive healthcare that allows intervention at early stages of disease development resulting in treatments with reduced health consequences at a lower financial burden
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| 7. |
- Barrenäs, Fredrik, et al.
(författare)
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Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-beta and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.
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| 8. |
- Bornelöv, Susanne, et al.
(författare)
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Different distribution of histone modifications in genes with unidirectional and bidirectional transcription and a role of CTCF and cohesin in directing transcription
- 2015
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several post-translational histone modifications are mainly found in gene promoters and are associated with the promoter activity. It has been hypothesized that histone modifications regulate the transcription, as opposed to the traditional view with transcription factors as the key regulators. Promoters of most active genes do not only initiate transcription of the coding sequence, but also a substantial amount of transcription of the antisense strand upstream of the transcription start site (TSS). This promoter feature has generally not been considered in previous studies of histone modifications and transcription factor binding.Results: We annotated protein-coding genes as bi- or unidirectional depending on their mode of transcription and compared histone modifications and transcription factor occurrences between them. We found that H3K4me3, H3K9ac, and H3K27ac were significantly more enriched upstream of the TSS in bidirectional genes compared with the unidirectional ones. In contrast, the downstream histone modification signals were similar, suggesting that the upstream histone modifications might be a consequence of transcription rather than a cause. Notably, we found well-positioned CTCF and RAD21 peaks approximately 60-80 bp upstream of the TSS in the unidirectional genes. The peak heights were related to the amount of antisense transcription and we hypothesized that CTCF and cohesin act as a barrier against antisense transcription.Conclusions: Our results provide insights into the distribution of histone modifications at promoters and suggest a novel role of CTCF and cohesin as regulators of transcriptional direction.
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| 9. |
- Cavalli, Marco, et al.
(författare)
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Studies of liver tissue identify functional gene regulatory elements associated to gene expression, type 2 diabetes, and other metabolic diseases
- 2019
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Ingår i: Human Genomics. - : Springer Science and Business Media LLC. - 1473-9542 .- 1479-7364. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background:Genome-wide association studies (GWAS) of diseases and traits have found associations to gene regions but not the functional SNP or the gene mediating the effect. Difference in gene regulatory signals can be detected using chromatin immunoprecipitation and next-gen sequencing (ChIP-seq) of transcription factors or histone modifications by aligning reads to known polymorphisms in individual genomes. The aim was to identify such regulatory elements in the human liver to understand the genetics behind type 2 diabetes and metabolic diseases.Methods: The genome of liver tissue was sequenced using 10X Genomics technology to call polymorphic positions. Using ChIP-seq for two histone modifications, H3K4me3 and H3K27ac, and the transcription factor CTCF, and our established bioinformatics pipeline, we detected sites with significant difference in signal between the alleles.Results:We detected 2329 allele-specific SNPs (AS-SNPs) including 25 associated to GWAS SNPs linked to liver biology, e.g., 4 AS-SNPs at two type 2 diabetes loci. Two hundred ninety-two AS-SNPs were associated to liver gene expression in GTEx, and 134 AS-SNPs were located on 166 candidate functional motifs and most of them in EGR1-binding sites.Conclusions:This study provides a valuable collection of candidate liver regulatory elements for further experimental validation.
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| 10. |
- Dabrowski, M. J., et al.
(författare)
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'True' null allele detection in microsatellite loci : a comparison of methods, assessment of difficulties and survey of possible improvements
- 2015
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Ingår i: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 15:3, s. 477-488
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Tidskriftsartikel (refereegranskat)abstract
- Null alleles are alleles that for various reasons fail to amplify in a PCR assay. The presence of null alleles in microsatellite data is known to bias the genetic parameter estimates. Thus, efficient detection of null alleles is crucial, but the methods available for indirect null allele detection return inconsistent results. Here, our aim was to compare different methods for null allele detection, to explain their respective performance and to provide improvements. We applied several approaches to identify the true' null alleles based on the predictions made by five different methods, used either individually or in combination. First, we introduced simulated true' null alleles into 240 population data sets and applied the methods to measure their success in detecting the simulated null alleles. The single best-performing method was ML-NullFreq_frequency. Furthermore, we applied different noise reduction approaches to improve the results. For instance, by combining the results of several methods, we obtained more reliable results than using a single one. Rule-based classification was applied to identify population properties linked to the false discovery rate. Rules obtained from the classifier described which population genetic estimates and loci characteristics were linked to the success of each method. We have shown that by simulating true' null alleles into a population data set, we may define a null allele frequency threshold, related to a desired true or false discovery rate. Moreover, using such simulated data sets, the expected null allele homozygote frequency may be estimated independently of the equilibrium state of the population.
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