| 1. |
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| 2. |
- de Vries, Paul S., et al.
(author)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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In: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Journal article (peer-reviewed)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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| 3. |
- de las Fuentes, Lisa, et al.
(author)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Journal article (peer-reviewed)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 4. |
- Feitosa, Mary F., et al.
(author)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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In: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Journal article (peer-reviewed)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 5. |
- Sung, Yun Ju, et al.
(author)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Journal article (peer-reviewed)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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| 6. |
- Ganesh, Santhi K., et al.
(author)
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Loci influencing blood pressure identified using a cardiovascular gene-centric array
- 2013
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:8, s. 1663-1678
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Journal article (peer-reviewed)abstract
- Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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| 7. |
- Lange, Leslie A, et al.
(author)
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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
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Journal article (peer-reviewed)abstract
- Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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| 8. |
- Rondonotti, E, et al.
(author)
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Small-bowel neoplasms in patients undergoing video capsule endoscopy: a multicenter European study
- 2008
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In: Endoscopy. - : Georg Thieme Verlag KG. - 1438-8812 .- 0013-726X. ; 40:6, s. 488-495
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Journal article (peer-reviewed)abstract
- Background and study aim: Small-bowel tumors account for 1%-3% of all gastrointestinal neoplasms. Recent studies with video capsule endoscopy (VCE) suggest that the frequency of these tumors may be substantially higher than previously reported. The aim of the study was to evaluate the frequency, clinical presentation, diagnostic/therapeutic work-up, and endoscopic appearance of small-bowel tumors in a large population of patients undergoing VCE. Patients and methods: Identification by a questionnaire of patients with VCE findings suggesting small-bowel tumors and histological confirmation of the neoplasm seen in 29 centers of 10 European Countries. Results: Of 5129 patients undergoing VCE, 124 (2.4%) had small-bowel tumors (112 primary, 12 metastatic). Among these patients, indications for VCE were: obscure gastrointestinal bleeding (108 patients), abdominal pain (9), search for primary neoplasm (6), diarrhea with malabsorption (1). The main primary small-bowel tumor type was gastrointestinal stromal tumor (GIST) (32%) followed by adenocarcinoma (20%) and carcinoid (15%); 66% of secondary small-bowel tumors were melanomas. Of the tumors, 80.6% were identified solely on the basis of VCE findings. 55 patients underwent WE as the third procedure after negative bidirectional endoscopy. The lesions were single in 89.5 % of cases, and multiple in 10.5%. Retention of the capsule occurred in 9.8% of patients with small-bowel tumors. After VICE, 54/124 patients underwent 57 other examinations before treatment; in these patients enteroscopy, when performed, showed a high diagnostic yield. Treatment was surgery in 95% of cases. Conclusions: Our data suggest that VCE detects small-bowel tumors in a small proportion of patients undergoing this examination, but the early use of this tool can shorten the diagnostic workup and influence the subsequent management of these patients.
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| 9. |
- Spada, C., et al.
(author)
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Colon capsule endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline
- 2012
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In: Endoscopy. - : Georg Thieme Verlag KG. - 1438-8812 .- 0013-726X. ; 44:5, s. 527-535
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Journal article (peer-reviewed)abstract
- PillCam colon capsule endoscopy (CCE) is an innovative noninvasive, and painless ingestible capsule technique that allows exploration of the colon without the need for sedation and gas insufflation. Although it is already available in European and other countries, the clinical indications for CCE as well as the reporting and work-up of detected findings have not yet been standardized. The aim of this evidence-based and consensus-based guideline, commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to furnish healthcare providers with a comprehensive framework for potential implementation of this technique in a clinical setting.
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| 10. |
- Spada, C., et al.
(author)
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Kolonkapselendoskopie: Leitlinie der Europäischen Gesellschaft für Gastrointestinale Endoskopie
- 2012
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In: Endoskopie Heute. - : Georg Thieme Verlag KG. - 0933-811X .- 1439-2577. ; 25:2, s. 145-154
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Journal article (peer-reviewed)abstract
- PillCam colon capsule endoscopy (CCE) is an innovative noninvasive, and painless ingestible capsule technique that allows exploration of the colon without the need for sedation and gas insufflation. Although it is already available in European and other countries, the clinical indications for CCE as well as the reporting and workup of detected findings have not yet been standardized. The aim of this evidence-based and consensus-based guideline, commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to furnish healthcare providers with a comprehensive framework for potential implementation of this technique in a clinical setting.
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| 11. |
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| 12. |
- Leenhardt, R., et al.
(author)
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Key research questions for implementation of artificial intelligence in capsule endoscopy
- 2022
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In: Therapeutic Advances in Gastroenterology. - : SAGE Publications. - 1756-283X .- 1756-2848. ; 15
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Journal article (peer-reviewed)abstract
- Background: Artificial intelligence (AI) is rapidly infiltrating multiple areas in medicine, with gastrointestinal endoscopy paving the way in both research and clinical applications. Multiple challenges associated with the incorporation of AI in endoscopy are being addressed in recent consensus documents. Objectives: In the current paper, we aimed to map future challenges and areas of research for the incorporation of AI in capsule endoscopy (CE) practice. Design: Modified three-round Delphi consensus online survey. Methods: The study design was based on a modified three-round Delphi consensus online survey distributed to a group of CE and AI experts. Round one aimed to map out key research statements and challenges for the implementation of AI in CE. All queries addressing the same questions were merged into a single issue. The second round aimed to rank all generated questions during round one and to identify the top-ranked statements with the highest total score. Finally, the third round aimed to redistribute and rescore the top-ranked statements. Results: Twenty-one (16 gastroenterologists and 5 data scientists) experts participated in the survey. In the first round, 48 statements divided into seven themes were generated. After scoring all statements and rescoring the top 12, the question of AI use for identification and grading of small bowel pathologies was scored the highest (mean score 9.15), correlation of AI and human expert reading-second (9.05), and real-life feasibility-third (9.0). Conclusion: In summary, our current study points out a roadmap for future challenges and research areas on our way to fully incorporating AI in CE reading.
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| 13. |
- Leenhardt, Romain, et al.
(author)
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Nomenclature and semantic descriptions of ulcerative and inflammatory lesions seen in Crohn’s disease in small bowel capsule endoscopy : An international Delphi consensus statement
- 2020
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In: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 8:1, s. 99-107
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Journal article (peer-reviewed)abstract
- Background: In the medical literature, the nomenclature and descriptions (ND) of small bowel (SB) ulcerative and inflammatory (U-I) lesions in capsule endoscopy (CE) are scarce and inconsistent. Inter-observer variability in interpreting these findings remains a major limitation in the assessment of the severity of mucosal lesions, which can impact negatively on clinical care, training and research on SB-CE. Objective: Focusing on SB-CE in Crohn’s disease (CD), our aim is to establish a consensus on the ND of U-I lesions. Methods: An international panel of experienced SB-CE readers was formed during the 2016 United European Gastroenterology Week meeting. A core group of five CE and inflammatory bowel disease (IBD) experts established an Internet-based, three-round Delphi consensus but did not participate in the voting process. The core group built illustrated questionnaires, including SB-CE still frames of U-I lesions from patients with documented CD. Twenty-seven other experts were asked to rate and comment on the different proposals for the ND of the most frequent SB U-I lesions. For each round, we used a 6-point rating scale (varying from ‘strongly disagree’ to ‘strongly agree’). The consensus was reached when at least 80 % of the voting members scored the statement within the ‘agree’ or ‘strongly agree’ categories. Results: A 100% participation rate was obtained for all the rounds. Consensual ND were reached for the following seven U-I lesions: aphthoid erosion, deep ulceration, superficial ulceration, stenosis, edema, hyperemia and denudation. Conclusion: Considering the most frequent SB U-I lesions seen in CE in CD, a consensual ND was reached by the international group of experts. These descriptions and names are useful not only for daily practice and medical education, but also for medical research.
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| 14. |
- Leighton, Jonathan A., et al.
(author)
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Capsule Endoscopy Is Superior to Small-bowel Follow-through and Equivalent to Ileocolonoscopy in Suspected Crohn's Disease
- 2014
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In: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-7714 .- 1542-3565. ; 12:4, s. 609-615
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Evaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohn's disease. METHODS: Eighty patients with signs and/or symptoms of small-bowel Crohn's disease (age, 10-65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT. RESULTS: The combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohn's disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone. CONCLUSIONS: CE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohn's disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396.
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| 15. |
- Smedsrud, P. H., et al.
(author)
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Kvasir-Capsule, a video capsule endoscopy dataset
- 2021
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 8:1
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Journal article (peer-reviewed)abstract
- Artificial intelligence (AI) is predicted to have profound effects on the future of video capsule endoscopy (VCE) technology. The potential lies in improving anomaly detection while reducing manual labour. Existing work demonstrates the promising benefits of AI-based computer-assisted diagnosis systems for VCE. They also show great potential for improvements to achieve even better results. Also, medical data is often sparse and unavailable to the research community, and qualified medical personnel rarely have time for the tedious labelling work. We present Kvasir-Capsule, a large VCE dataset collected from examinations at a Norwegian Hospital. Kvasir-Capsule consists of 117 videos which can be used to extract a total of 4,741,504 image frames. We have labelled and medically verified 47,238 frames with a bounding box around findings from 14 different classes. In addition to these labelled images, there are 4,694,266 unlabelled frames included in the dataset. The Kvasir-Capsule dataset can play a valuable role in developing better algorithms in order to reach true potential of VCE technology.
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| 16. |
- Smith, Gustav, et al.
(author)
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The Impact of Ancestry and Common Genetic Variants on QT Interval in African Americans.
- 2012
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In: Circulation: Cardiovascular Genetics. - 1942-325X. ; 5:6, s. 647-655
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Journal article (peer-reviewed)abstract
- BACKGROUND: -Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death (SCD) and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. METHODS AND RESULTS: -First, individual estimates of African and European ancestry were inferred from genome-wide single nucleotide polymorphism (SNP) data in seven population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from electrocardiograms. Second, imputation was performed for 2.8 million SNPs and a genome-wide association (GWA) study of QT interval performed in ten cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (p=0.94). Genome-wide significant associations (p<2.5x10(-8)) were identified with SNPs at two loci, upstream of the genes NOS1AP (rs12143842, p=2x10(-15)) and ATP1B1 (rs1320976, p=2x10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low p-values (p<10(-5)) were observed for SNPs at several other loci previously identified in GWA studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF and PLN. CONCLUSIONS: -We observed no difference in duration of cardiac repolarization with global genetic indices of African ancestry. In addition, our GWA study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include African Americans.
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Dutkay, Dorin Ervin, et al.
(author)
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Decomposition of wavelet representations and Martin boundaries
- 2012
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In: Journal of Functional Analysis. - : Elsevier BV. - 0022-1236 .- 1096-0783. ; 262:3, s. 1043-1061
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Journal article (peer-reviewed)abstract
- We study a decomposition problem for a class of unitary representations associated with wavelet analysis, wavelet representations, but our framework is wider and has applications to multi-scale expansions arising in dynamical systems theory for non-invertible endomorphisms. Our main results offer a direct integral decomposition for the general wavelet representation, and we solve a question posed by Judith Packer. This entails a direct integral decomposition of the general wavelet representation. We further give a detailed analysis of the measures contributing to the decomposition into irreducible representations. We prove results for associated Martin boundaries, relevant for the understanding of wavelet filters and induced random walks, as well as classes of harmonic functions. Published by Elsevier Inc.
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| 21. |
- Flannick, Jason, et al.
(author)
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Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1380-1380
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Journal article (peer-reviewed)abstract
- Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
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| 22. |
- Haraldsson, E, et al.
(author)
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Endoscopic classification of the papilla of Vater. Results of an inter- and intraobserver agreement study
- 2017
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In: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 5:4, s. 504-510
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Journal article (peer-reviewed)abstract
- Background: Many endoscopists acknowledge that the appearance of the papilla of Vater seems to affect biliary cannulation. To assess the association between the macroscopic appearance of the papilla and biliary cannulation and other related clinical issues, a system is needed to define the appearance of the papilla. Objective: The purpose of this study was to validate an endoscopic classification of the papilla of Vater by assessing the interobserver and intraobserver agreements among endoscopist with varying experience. Methods: An endoscopic classification, based on pictures captured from 140 different papillae, containing four types of papillae was proposed. The four types are (a) Type 1: regular papilla, no distinctive features, ‘classic appearance’; (b) Type 2: small papilla, often flat, with a diameter ≤ 3 mm (approximately 9 Fr); (c) Type 3: protruding or pendulous papilla, a papilla that is standing out, protruding or bulging into the duodenal lumen or sometimes hanging down, pendulous with the orifice oriented caudally; and (d) Type 4: creased or ridged papilla, where the ductal mucosa seems to extend distally, rather out of the papillary orifice, either on a ridge or in a crease. To assess the level of interobserver agreement, a web-based survey was sent out to 18 endoscopists, containing 50 sets of still images of the papilla, distributed between the four different types. Three months later a follow-up survey, with images from the first survey was sent to the same endoscopists. Results: Interobserver agreement was substantial (κ = 0.62, 95% confidence interval (CI) 0.58–0.65) and were similar for both experts and non-experts. The intraobserver agreement assessed with the second survey was also substantial (κ = 0.66, 95% CI 0.59–0.72). Conclusion: The proposed endoscopic classification of the papilla of Vater seems to be easy to use, irrespective of the level of experience of the endoscopist. It carries a substantial inter- and intraobserver agreement and now the clinical relevance of the four different papilla types awaits to be determined.
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| 23. |
- Koulaouzidis, Anastasios, et al.
(author)
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Association Between Fecal Calprotectin Levels and Small-bowel Inflammation Score in Capsule Endoscopy : A Multicenter Retrospective Study
- 2016
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In: Digestive Diseases and Sciences. - : Springer Science and Business Media LLC. - 1573-2568 .- 0163-2116. ; 61:7, s. 2033-2040
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Journal article (peer-reviewed)abstract
- BACKGROUND: Accurate inflammation reporting in capsule endoscopy (CE) is important for diagnosis and monitoring of treatment of inflammatory bowel disease (IBD). Fecal calprotectin (FC) is a highly specific biomarker of gut inflammation. Lewis score (LS) was developed to standardize quantification of inflammation in small-bowel (SB) CE images.GOALS: Multicenter retrospective study aiming to investigate correlation between LS and FC in a large group of patients undergoing CE for suspected or known small-bowel IBD, and to develop a model for prediction of CE results (LS) based on FC levels.STUDY: Five academic centers and a district general hospital offering CE in UK, Finland, Sweden, Canada, and Israel. In total, 333 patients were recruited. They had small-bowel CE and FC done within 3 months.RESULTS: Overall, correlation between FC and LS was weak (r s: 0.232, P < 0.001). When two clinically significant FC thresholds (100 and 250 μg/g) were examined, the r s between FC and LS was 0.247 (weak) and 0.337 (moderate), respectively (P = 0.307). For clinically significant (LS ≥ 135) or negative (LS < 135) for SB inflammation, ROC curves gave an optimum cutoff point of FC 76 μg/g with sensitivity 0.59 and specificity 0.41.LIMITATIONS: Retrospective design.CONCLUSIONS: LS appears to show low correlation with FC as well as other serology markers of inflammation. FC does not appear to be a reliable biomarker for significant small-bowel inflammation. Nevertheless, FC level ≥ 76 μg/g may be associated with appreciable visual inflammation on small-bowel CE in patients with negative prior diagnostic workup.
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| 24. |
- Koulaouzidis, Anastasios, et al.
(author)
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KID Project : an internet-based digital video atlas of capsule endoscopy for research purposes
- 2017
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In: Endoscopy International Open. - : Georg Thieme Verlag KG. - 2364-3722 .- 2196-9736. ; 5:6, s. 477-483
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: Capsule endoscopy (CE) has revolutionized small-bowel (SB) investigation. Computational methods can enhance diagnostic yield (DY); however, incorporating machine learning algorithms (MLAs) into CE reading is difficult as large amounts of image annotations are required for training. Current databases lack graphic annotations of pathologies and cannot be used. A novel database, KID, aims to provide a reference for research and development of medical decision support systems (MDSS) for CE.METHODS: Open-source software was used for the KID database. Clinicians contribute anonymized, annotated CE images and videos. Graphic annotations are supported by an open-access annotation tool (Ratsnake). We detail an experiment based on the KID database, examining differences in SB lesion measurement between human readers and a MLA. The Jaccard Index (JI) was used to evaluate similarity between annotations by the MLA and human readers.RESULTS: The MLA performed best in measuring lymphangiectasias with a JI of 81 ± 6 %. The other lesion types were: angioectasias (JI 64 ± 11 %), aphthae (JI 64 ± 8 %), chylous cysts (JI 70 ± 14 %), polypoid lesions (JI 75 ± 21 %), and ulcers (JI 56 ± 9 %).CONCLUSION: MLA can perform as well as human readers in the measurement of SB angioectasias in white light (WL). Automated lesion measurement is therefore feasible. KID is currently the only open-source CE database developed specifically to aid development of MDSS. Our experiment demonstrates this potential.
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| 25. |
- Koulaouzidis, Anastasios, et al.
(author)
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Macroscopic findings in collagenous colitis : A multi-center, retrospective, observational cohort study
- 2017
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In: Annals of Gastroenterology. - : Hellenic Society of Gastroenterology. - 1108-7471 .- 1792-7463. ; 30:3, s. 309-314
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Journal article (peer-reviewed)abstract
- Background Collagenous colitis (CC) is by definition a histological diagnosis. However, colonoscopy often reveals characteristic endoscopic findings. The aim of this study was to evaluate the frequency and type of endoscopic findings in patients diagnosed with CC in 4 participating centers. Methods This was a retrospective study; the databases of 2 university hospitals in Edinburgh (Scotland) and Malmö (Sweden), and 2 district general hospitals in Tomelloso (Spain) and Gateshead (England) were interrogated for patients diagnosed with CC between May 2008 and August 2013. Endoscopy reports and images were retrieved and reviewed; data on lesions, sedation, bowel preparation and endoscopist experience were abstracted. Categorical data are reported as mean±SD. Fischer’s exact, chi-square and t (unpaired) tests were used to compare datasets. A two-tailed P-value of <0.05 was considered statistically significant. Results 607 patients (149 male, mean age 66.9±12.25 years) were diagnosed with CC. A total of 108/607 (17.8%) patients had one or more suggestive endoscopy findings: i.e., mucosal erythema/edema, 91/607 (15%); linear colonic mucosal defects, 12/607 (2%); or mucosal scarring, 5/607 (0.82%). For colonic mucosa erythema, there was no difference in the odds of finding erythema with the use of different bowel preparation methods (P=0.997). For colonic mucosal defects there was some evidence (P=0.005) that patients colonoscoped by experienced endoscopists had 87% less odds of developing such defects. Moreover, there was evidence that analgesia reduced the odds of developing mucosal defects by 84%. Conclusion A significant minority of patients with CC have endoscopic findings in colonoscopy. The description of such findings appears to be related to the endoscopist’s experience.
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| 26. |
- Koulaouzidis, Anastasios, et al.
(author)
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Novel experimental and software methods for image reconstruction and localization in capsule endoscopy
- 2018
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In: Endoscopy International Open. - : Georg Thieme Verlag KG. - 2364-3722 .- 2196-9736. ; 6:2, s. 205-210
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Journal article (peer-reviewed)abstract
- Background and study aims : Capsule endoscopy (CE) is invaluable for minimally invasive endoscopy of the gastrointestinal tract; however, several technological limitations remain including lack of reliable lesion localization. We present an approach to 3D reconstruction and localization using visual information from 2D CE images.Patients and methods : Colored thumbtacks were secured in rows to the internal wall of a LifeLike bowel model. A PillCam SB3 was calibrated and navigated linearly through the lumen by a high-precision robotic arm. The motion estimation algorithm used data (light falling on the object, fraction of reflected light and surface geometry) from 2D CE images in the video sequence to achieve 3D reconstruction of the bowel model at various frames. The ORB-SLAM technique was used for 3D reconstruction and CE localization within the reconstructed model. This algorithm compared pairs of points between images for reconstruction and localization.Results: As the capsule moved through the model bowel 42 to 66 video frames were obtained per pass. Mean absolute error in the estimated distance travelled by the CE was 4.1 ± 3.9 cm. Our algorithm was able to reconstruct the cylindrical shape of the model bowel with details of the attached thumbtacks. ORB-SLAM successfully reconstructed the bowel wall from simultaneous frames of the CE video. The "track" in the reconstruction corresponded well with the linear forwards-backwards movement of the capsule through the model lumen.Conclusion: The reconstruction methods, detailed above, were able to achieve good quality reconstruction of the bowel model and localization of the capsule trajectory using information from the CE video and images alone.
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| 27. |
- Logan, Leslie, et al.
(author)
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Structural framework and timing of the Pahtohavare Cu ± Au deposits, Kiruna mining district, Sweden
- 2023
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In: Solid Earth. - : Copernicus Publications. - 1869-9510 .- 1869-9529. ; 14:7, s. 763-784
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Journal article (peer-reviewed)abstract
- As part of the larger mineral systems approach to Cu-bearing mineralization in northern Norrbotten, this study utilizes structural geology to set the classic Pahtohavare Cu ± Au deposits into an up-to-date tectonic framework. The Pahtohavare Cu ± Au deposits, situated only 5 km southwest of the Kiirunavaara world-class iron oxide–apatite (IOA) deposit, have a dubious timing, and their link to IOA formation is not constrained. The study area contains both epigenic Cu ± Au (Pahtohavare) and iron oxide–copper–gold (IOCG; Rakkurijärvi) mineral occurrences which are hosted in bedrock that has been folded and bound by two shear zones trending northeast to southwest and northwest to southeast to the east and southwest, respectively. Structural mapping and petrographic investigation of the area reveal a noncylindrical, SE-plunging anticline. The cleavage measurements mirror the fold geometry, which characterizes the fold as F2 associated with the late phase of the Svecokarelian orogeny. Porphyroclasts with pressure shadows, mylonitic fabrics, and foliation trails in porphyroblasts indicate S0/S1 is a tectonic fabric. The epigenetic Pahtohavare Cu ± Au mineralization sits in brittle–ductile structures that cross-cut an earlier foliation and the F2 fold, indicating that the timing of the deposits occurred syn- to post-F2 folding, at least ca. 80 Myr after the Kiirunavaara IOA formation. A 3D model and cross-sections of the Pahtohavare–Rakkurijärvi area and a new structural framework of the district are presented and used to suggest that the shear zones bounding the area are likely reactivated early structures that have played a critical role in ore formation in the Kiruna mining district.
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| 28. |
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| 29. |
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| 30. |
- Toth, Ervin, et al.
(author)
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Intestinal lymphangiectasia.
- 2006
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In: Atlas of video capsule endoscopy. - 3540231285 ; 5.2, s. 101-106
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Book chapter (other academic/artistic)
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| 31. |
- Toth, Ervin, et al.
(author)
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Video capsule colonoscopy in routine clinical practice
- 2017
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In: Annals of Translational Medicine. - : AME Publishing Company. - 2305-5839 .- 2305-5847. ; 5:9
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Journal article (peer-reviewed)abstract
- Background: Colon capsule endoscopy (CCE) offers direct mucosal visualisation without sedation or gas insufflation required in conventional colonoscopy (CC). However, evidence for the role of CCE as an adjunct or alternative to CC remains equivocal. In this observational cohort study, we report our experience of using CCE to investigate patients with suspected colon pathology at a tertiary referral centre. Methods: From 2007-2015, consecutive patients requiring colonoscopy were recruited from a tertiary care centre in Malmo, Sweden. Data collected: patient demographics, indication for CCE, findings, bowel cleansing, colon transit time (CTT) and completeness of colon examination. Results: Seventy-seven patients (57 F/20 F, median age 56 years) were included. The reason for CCE was previously incomplete or refused CC in 39 and 26 cases, and follow up of previous findings in 12 cases, respectively. The main clinical indications were gastrointestinal (GI) bleeding (n=28; 36%) and suspected inflammatory bowel disease (IBD) or follow-up of known IBD (n=23; 30%). CCE was complete in 58/77 (75%) patients. In 3 patients the colon was not reached; in the other 16, the capsule reached the rectum (n=4), sigmoid (n=6), descending colon (n=5) and transverse colon (n=1). Findings were: normal CCE (n=15; 19%) colonic diverticula (n=29; 38%), polyps (n=17; 22%), active IBD (n=12; 16%), haemorrhoids (n=8; 10%), colonic angioectasia (n=4; 5%) and cancer (n=1; 1%). Small-bowel findings were recorded in 8 (10%) patients. All patients tolerated bowel preparation and CCE well. Two patients with an ulcerated small-bowel stricture and cancer respectively experienced temporary capsule retention with spontaneous resolution. Conclusions: CCE is a well-tolerated alternative to CC, but requires technological improvement and optimisation of clinical practice to meet current reference standards. Although further technical development is required, CCE may complement or even replace CC for certain clinical indications.
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| 32. |
- Vasilakakis, Michael, et al.
(author)
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Follow-up on: optimizing lesion detection in small bowel capsule endoscopy and beyond: from present problems to future solutions
- 2019
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In: Expert Review of Gastroenterology and Hepatology. - : Informa UK Limited. - 1747-4124 .- 1747-4132. ; 13:2, s. 129-141
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Journal article (peer-reviewed)abstract
- Introduction: This review presents noteworthy advances in clinical and experimental Capsule Endoscopy (CE), focusing on the progress that has been reported over the last 5 years since our previous review on the subject. Areas covered: This study presents the commercially available CE platforms, as well as the advances made in optimizing the diagnostic capabilities of CE. The latter includes recent concept and prototype capsule endoscopes, medical approaches to improve diagnostic yield, and progress in software for enhancing visualization, abnormality detection, and lesion localization. Expert commentary: Currently, moving through the second decade of CE evolution, there are still several open issues and remarkable challenges to overcome.
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| 33. |
- Yung, Diana E., et al.
(author)
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Capsule endoscopy in young patients with iron deficiency anaemia and negative bidirectional gastrointestinal endoscopy
- 2017
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In: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 5:7, s. 974-981
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Journal article (peer-reviewed)abstract
- Background: Recent data imply young patients (age ≤50 years) undergoing small-bowel (SB) capsule endoscopy (CE) for iron deficiency anaemia (IDA) show higher diagnostic yield (DY) for sinister pathology. We aimed to investigate DY of CE in a large cohort of young IDA patients, and evaluate factors predicting significant SB pathology. Materials and methods: This was a retrospective, multicentre study (2010–2015) in consecutive, young patients (≤50 years) from 18 centres/12 countries, with negative bidirectional gastrointestinal (GI) endoscopy undergoing SBCE for IDA. Exclusion criteria: previous/ongoing obscure-overt GI bleeding; age <19 or >50 years; comorbidities associated with IDA. Data retrieved: SBCE indications; prior investigations; medications; SBCE findings; final diagnosis. Clinical and laboratory data were analysed by multivariate logistic regression. Results: Data on 389 young IDA patients were retrieved. In total, 169 (43.4%) were excluded due to incomplete clinical data; data from 220 (122F/98M; mean age 40.5 ± 8.6 years) patients were analysed. Some 71 patients had at least one clinically significant SBCE finding (DY: 32.3%). They were divided into two groups: neoplastic pathology (10/220; 4.5%), and non-neoplastic but clinically significant pathology (61/220; 27.7%). The most common significant but non-neoplastic pathologies were angioectasias (22/61) and Crohn’s disease (15/61). On multivariate analysis, weight loss and lower mean corpuscular volume(MCV) were associated with significant SB pathology (OR: 3.87; 95%CI: 1.3–11.3; p = 0.01; and OR: 0.96; 95%CI: 0.92–0.99; p = 0.03; respectively). Our model also demonstrates association between use of antiplatelets and significant SB pathology, although due to the small number of patients, definitive conclusions cannot be drawn. Conclusion: In IDA patients ≤50 years with negative bidirectional GI endoscopy, overall DY of SBCE for clinically significant findings was 32.3%. Some 5% of our cohort was diagnosed with SB neoplasia; lower MCV or weight loss were associated with higher DY for SB pathology.
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| 34. |
- Yung, Diana E., et al.
(author)
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Clinical outcomes of negative small-bowel capsule endoscopy for small-bowel bleeding : A systematic review and meta-analysis
- 2017
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In: Gastrointestinal Endoscopy. - : Elsevier BV. - 0016-5107. ; 85:2, s. 2-317
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Journal article (peer-reviewed)abstract
- Background and Aims: Small-bowel bleeding is the primary indication for capsule endoscopy (CE). Many experts advocate a "watch-and-wait" policy in negative CE. This meta-analysis examines the odds of rebleeding after negative index CE and the impact on long-term follow-up. Methods: A comprehensive literature search identified articles examining the rebleeding rate after negative CE. Demographic and clinical information with emphasis on outcomes was retrieved, pooled, and analyzed. Heterogeneity among studies was assessed using the I2 statistic. A random effects model was used as the pooling method because of high heterogeneity. Risk of bias was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. The primary outcome evaluated was the pooled odds ratios (ORs) for rebleeding after a negative CE for obscure GI bleeding (OGIB). Results: Twenty-six studies with 3657 patients were included. The pooled rate of rebleeding after negative CE was .19 (95% CI, .14-.25; . P < .0001). The pooled OR of rebleeding was .59 (95% CI, .37-.95; . P < .001). The effect was more pronounced in studies with a short follow-up (OR, .47; 95% CI, .24-.94; . P < .001). There was no statistically significant difference in rebleeding after CE for occult and overt OGIB. Prospective studies showed a lower OR of rebleeding of .24 (95% CI, .08-.73; . P = .01). Most studies were high quality. Conclusions: Our analysis shows that negative CE provides adequate evidence of a subsequently low risk of rebleeding. Such patients can therefore be safely managed with watchful waiting. However, patients who rebleed after 2 years may need to be investigated for a new source of blood loss.
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| 35. |
- Yung, Diana E, et al.
(author)
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Clinical validity of flexible spectral imaging color enhancement (FICE) in small-bowel capsule endoscopy : a systematic review and meta-analysis
- 2017
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In: Endoscopy. - : Georg Thieme Verlag KG. - 0013-726X .- 1438-8812. ; 49:3, s. 258-269
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Research review (peer-reviewed)abstract
- Patients and methods A comprehensive literature search was conducted. We measured pooled rate of lesion visualization improvement and improvement in lesion detection comparing FICE settings 1 – 3 and WLE, for angioectasias and ulcers/erosions. Pooled results were derived using the random-effects model because of high heterogeneity as measured by I 2. Repeated-measures analysis of variance (ANOVA) was used to measure differences in lesion detection between WLE and the three FICE modes. Results 13 studies were analyzed. All studies used the PillCam SB 1 and/or SB 2 devices. Most used experienced readers. Improvement in delineation had been investigated in 4 studies; in the 3 studies entered into the meta-analysis, using FICE setting 1, 89 % of angioectasias and 45 % of ulcer/erosions were considered to show improved delineation. For FICE settings 2 and 3, small proportions of images showed improved delineation. Heterogeneity of studies was high with I 2 > 90 % in 4/6 analyses. Lesion detection had been investigated in 10 studies; meta-analysis included 5 studies. Lesion detection did not differ significantly between any of the FICE modes and WLE. Conclusions Overall, the use of the three FICE modes did not significantly improve delineation or detection rate in SBCE. In pigmented lesions, FICE setting 1 performed better in lesion delineation and detection.
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| 36. |
- Zimmermannova, Olga, et al.
(author)
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Restoring tumor immunogenicity with dendritic cell reprogramming
- 2023
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In: Science Immunology. - 2470-9468. ; 8:85
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Journal article (peer-reviewed)abstract
- Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8 + T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8 + T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
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