| 1. |
- Romagnoni, A, et al.
(författare)
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Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
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Tidskriftsartikel (refereegranskat)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
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| 2. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 3. |
- Hu, M., et al.
(författare)
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Exploration of signals of positive selection derived from genotype-based human genome scans using re-sequencing data
- 2012
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:5, s. 665-674
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated whether regions of the genome showing signs of positive selection in scans based on haplotype structure also show evidence of positive selection when sequence-based tests are applied, whether the target of selection can be localized more precisely, and whether such extra evidence can lead to increased biological insights. We used two tools: simulations under neutrality or selection, and experimental investigation of two regions identified by the HapMap2 project as putatively selected in human populations. Simulations suggested that neutral and selected regions should be readily distinguished and that it should be possible to localize the selected variant to within 40 kb at least half of the time. Re-sequencing of two ∼300 kb regions (chr4:158Mb and chr10:22Mb) lacking known targets of selection in HapMap CHB individuals provided strong evidence for positive selection within each and suggested the micro-RNA gene hsa-miR-548c as the best candidate target in one region, and changes in regulation of the sperm protein gene SPAG6 in the other.
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| 4. |
- Monz, B, et al.
(författare)
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Patient-reported impact of urinary incontinence - Results from treatment seeking women in 14 European countries
- 2005
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Ingår i: Maturitas. - : Elsevier BV. - 1873-4111 .- 0378-5122. ; 52:Suppl 2, s. 24-34
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To describe the patient-reported impact of urinary incontinence (UI) in treatment-seeking women in Europe. Design: PURE was a non-interventional, observational study, which aimed to describe the direct costs of treatment for European women seeking treatment for UI. A secondary Study objective was to describe the impact of UI on health-related quality of life (HRQoL) by UI subtype and severity of disease. This paper presents the results from quality of life assessments as well as bothersomeness and interference with daily activities from the first study observation. Subjects: Nine thousand four hundred and eighty-seven European women who had UI symptoms in the last 12 months were enrolled. Their UI symptoms were frequently those defined as mixed urinary incontinence (MUI) and were moderate to severe in nature. Measurements: HRQoL was assessed at the first observation using the urinary Incontinence-specific Quality of Life Questionnaire (I-QOL) and the EQ-5D, a generic quality of life questionnaire. Data collected from EQ-5D provided insight into the patients' general health perception, while the I-QOL data indicated how affected the women were about their UI symptoms. Higher EQ-5D and I-QOL scores represent better quality of life. Patients were asked to indicate how much UI symptoms limited selected activities and to indicate the degree to which they found their symptoms to be bothersome. Results: Overall, the median self-rated health status on the EQ-5D visual analogue scale (VAS) was 70.0 and the median EQ-5D health state index was 0.85, with small but noticeable differences observed between countries. Of the five health dimensions of the EQ-5D, patients' self-care appeared to be the least affected by UI, with fewer than 10% of the women reporting that they had some problems. Between 20 and 40% of patients had some problems with their mobility and usual activities, or had pain/discomfort or anxiety/depression. However, the impact of existing co-morbidity was not assessed and may have affected some women's scoring of the EQ-5D domains. The mean total I-QOL score overall was 57.7 and of the three subscales of the I-QOL, psychosocial impact had the highest overall scores, representing fewer problems, with lower scores observed for the avoidance and limiting behaviour subscale, and even lower scores for the social embarrassment subscale. The greatest patient-reported impact of UI symptoms on activities was on exercise, with more than 45% of patients moderately to totally limited in this activity. In most of the countries, more than 60% of the women reported that they were moderately to extremely bothered by their UI symptoms. Conclusions: There was considerable impact of UI on HRQoL in a treatment seeking population, as demonstrated by the disease-specific quality of life scale and by the high percentage of patients who were bothered by their symptoms.
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| 5. |
- Sykes, D, et al.
(författare)
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Characteristics of female outpatients with urinary incontinence participating in a 6-month observational study in 14 European countries
- 2005
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Ingår i: Maturitas. - : Elsevier BV. - 1873-4111 .- 0378-5122. ; 52:Suppl 2, s. 13-23
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe the characteristics, of women seeking treatment for Symptoms of urinary incontinence (UI) in European countries. Design: Prospective urinary incontinence research (PURE) was a 6-month, observational, pan-European Study, primarily aimed at determining the direct costs of urinary incontinence treatment. The secondary objectives of PURE were to describe the impact of UI on health-related quality of life (HRQoL) in treatment seeking patients and to illustrate the treatment patterns For UI in Europe. Setting: One thousand and Fifty-five physicians from 14 European Countries, including general practitioners (GPs), gynaecologists, urologists and geriatricians, observed women seeking treatment For their UI and recorded data at the first observation and then prospectively at 3 and 6 months after the first observation during the normal course of therapy. Subjects: Women of at least 18 years of age who had experienced urinary leakage in the 12 months prior to enrolment in the study, who were seeking treatment or under treatment for UI and who presented within the normal,11 Course of UI care were included in the 6 months study. The first observation characteristics of the patients are described here. Methods: Demographic characteristics, as well as disease and treatment status at first observation were explored using descriptive summary statistics to gain an understanding Of the Population studied. Results: In total, 9487 women took part in PURE, with the largest patient groups from Germany, Spain and the UK/Ireland. The majority of women were post-menopausal and had a mean age of 60.7 years, were not current smokers and tended to be overweight (BMI > 25.0). Overall, mixed UI symptoms were more common than SUI and UUI as defined by clinical opinion (SUI 38%, MUI 42% and UUI 18%), and by a two-item questionnaire, the S/UIQ (SUI 29%. MUI 58% and UUI 13%). Around half of the patients (48%) suffered from their symptoms for less than 2 years before consulting a physician; 28% delayed seeking treatment for 3-5 years, with 13% waiting for 6-10 years and the remaining 11% waiting for 11 or more years. Conclusions: Some of the described patients' characteristics may provide important information to clinicians to enable them to take a more active approach to case-finding, which Will ultimately benefit the incontinent patient.
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| 8. |
- Butler, Geraldine, et al.
(författare)
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Evolution of pathogenicity and sexual reproduction in eight Candida genomes.
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 459:7247, s. 657-62
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Tidskriftsartikel (refereegranskat)abstract
- Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.
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