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| 4. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 5. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 12. |
- de Jong, S, et al.
(författare)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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| 13. |
- Jonsson, Lina, 1982, et al.
(författare)
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Characterisation of age and polarity at onset in bipolar disorder
- 2021
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Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
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Tidskriftsartikel (refereegranskat)abstract
- Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
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| 15. |
- Witt, S. H., et al.
(författare)
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Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia
- 2017
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P = 4.42 x 10(-7)) and PKP4 (P = 8.67 x 10(-7)); and gene-set analysis yielded a significant finding for exocytosis (GO: 0006887, PFDR = 0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (r(g) = 0.28 [P = 2.99 x 10(-3)]), SCZ (r(g) = 0.34 [P = 4.37 x 10(-5)]) and MDD (r(g) = 0.57 [P = 1.04 x 10(-3)]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
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| 19. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 21. |
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| 22. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 25. |
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| 26. |
- Jia, X. M., et al.
(författare)
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Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:9, s. 5239-5250
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 x 10(-4)), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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| 29. |
- Coleman, M P, et al.
(författare)
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Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership) : an analysis of population-based cancer registry data
- 2011
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 377:9760, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cancer survival is a key measure of the effectiveness of health-care systems. Persistent regional and international differences in survival represent many avoidable deaths. Differences in survival have prompted or guided cancer control strategies. This is the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival. METHODS: Data from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast (women), or ovarian cancer during 1995-2007, with follow-up to Dec 31, 2007. Data quality control and analyses were done centrally with a common protocol, overseen by external experts. We estimated 1-year and 5-year relative survival, constructing 252 complete life tables to control for background mortality by age, sex, and calendar year. We report age-specific and age-standardised relative survival at 1 and 5 years, and 5-year survival conditional on survival to the first anniversary of diagnosis. We also examined incidence and mortality trends during 1985-2005. FINDINGS: Relative survival improved during 1995-2007 for all four cancers in all jurisdictions. Survival was persistently higher in Australia, Canada, and Sweden, intermediate in Norway, and lower in Denmark, England, Northern Ireland, and Wales, particularly in the first year after diagnosis and for patients aged 65 years and older. International differences narrowed at all ages for breast cancer, from about 9% to 5% at 1 year and from about 14% to 8% at 5 years, but less or not at all for the other cancers. For colorectal cancer, the international range narrowed only for patients aged 65 years and older, by 2-6% at 1 year and by 2-3% at 5 years. INTERPRETATION: Up-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older. FUNDING: Department of Health, England; and Cancer Research UK.
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| 30. |
- Mullins, Niamh, et al.
(författare)
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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
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Tidskriftsartikel (refereegranskat)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
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| 31. |
- Weber, H., et al.
(författare)
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The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis
- 2014
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 24:1, s. 65-85
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Tidskriftsartikel (refereegranskat)abstract
- NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ. interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. (C) 2013 Elsevier B.V. and ECNP. All rights reserved.
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| 32. |
- Rystedt, J. M.L., et al.
(författare)
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Routine versus selective intraoperative cholangiography during cholecystectomy: systematic review, meta-analysis and health economic model analysis of iatrogenic bile duct injury
- 2021
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Ingår i: BJS open. - Oxford : Oxford University Press (OUP). - 2474-9842. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bile duct injury (BDI) is a severe complication following cholecystectomy. Early recognition and treatment of BDI has been shown to reduce costs and improve patients' quality of life. The aim of this study was to assess the effect and cost-effectiveness of routine versus selective intraoperative cholangiography (IOC) in cholecystectomy. Methods: A systematic review and meta-analysis, combined with a health economic model analysis in the Swedish setting, was performed. Costs per quality-adjusted life-year (QALY) for routine versus selective IOC during cholecystectomy for different scenarios were calculated. Results: In this meta-analysis, eight studies with more than 2 million patients subjected to cholecystectomy and 9000 BDIs were included. The rate of BDI was estimated to 0.36 per cent when IOC was performed routinely, compared with to 0.53 per cent when used selectively, indicating an increased risk for BDI of 43 per cent when IOC was used selectively (odds ratio 1.43, 95 per cent c.i. 1.22 to 1.67). The model analysis estimated that seven injuries were avoided annually by routine IOC in Sweden, a population of 10 million. Over a 10-year period, 33 QALYs would be gained at an approximate net cost of (sic)808 000 , at a cost per QALY of about (sic)24 900. Conclusion: Routine IOC during cholecystectomy reduces the risk of BDI compared with the selective strategy and is a potentially cost-effective intervention.
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| 35. |
- Adolfsson, J., et al.
(författare)
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QCD challenges from pp to A–A collisions
- 2020
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Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-6001 .- 1434-601X. ; 56:11
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Forskningsöversikt (refereegranskat)abstract
- This paper is a write-up of the ideas that were presented, developed and discussed at the third International Workshop on QCD Challenges from pp to A–A, which took place in August 2019 in Lund, Sweden (Workshop link: https://indico.lucas.lu.se/event/1214/). The goal of the workshop was to focus on some of the open questions in the field and try to come up with concrete suggestions for how to make progress on both the experimental and theoretical sides. The paper gives a brief introduction to each topic and then summarizes the primary results.
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| 41. |
- Gronberg, H, et al.
(författare)
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The risk-based STHLM3 model to improve prostate cancer testing in men 50-69 years: Further health, economic, and clinic evaluation
- 2016
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Ingår i: JOURNAL OF CLINICAL ONCOLOGY. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 34:2
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- 36 Background: Prostate-specific antigen (PSA) is used to screen for prostate cancer but suffers from a high false-positive rate that translates into unnecessary prostate biopsies and over-diagnosis of low-risk prostate cancers. We aimed to develop a model for prostate cancer screening with better test characteristics than PSA. Methods: STHLM3 is a prospective, population-based, paired screen-positive diagnostic study. It investigates whether the predefined STHLM3 model, a combination of 6 plasma protein biomarkers (PSA, free-PSA, intact-PSA, HK2, MIC-1, and MSMB), genetic polymorphisms (232 SNPs), and clinical variables (age, family history, previous biopsies, DRE, and prostate volume) can substantially reduce the proportion of men biopsied while maintaining the same sensitivity to diagnose Gleason score ≥ 7 prostate cancer as PSA ≥3 ng/ml. In addition, a health economic evaluation was performed comparing the STHLM3 model with current clinical practice in Stockholm. Results: 58,818 men without prostate cancer aged 50-69, participated in the STHLM3 study, with 6,700 undergoing subsequent prostate biopsy. The STHLM3 model performed significantly better (p<0.001) than PSA for detecting GS ≥7 cancers, increasing the Area Under the Curve from 0.56 to 0.74. All variables used in the STHLM3 Model were significantly associated with Gleason score ≥7 prostate cancers (p<0.05) in a multiple logistic regression model. Using the same sensitivity as PSA ≥3 ng/ml to diagnose Gleason score ≥7 prostate cancer, the STHLM3 model reduced the number of biopsies by 32% (95% CI 24%-39%) and avoided 44% (95% CI; 35%-54%) of the negative biopsies. The number of Gleason score 6 cancers was reduced by 17% (95% CI; 7%-26%). Positive ICER for the STHLM3 model was seen in all models of the health economic analysis. Conclusions: The STHLM3 model reduces unnecessary biopsies without compromising the ability to diagnose Gleason score ≥7 prostate cancer in a cost-efficient way. This is a significant step towards personalized risk-based prostate cancer diagnostic programs. Clinical trial information: ISRCTN84445406.
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| 45. |
- Lindström, Sara, et al.
(författare)
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Comprehensive genetic evaluation of common E-cadherin sequence variants and prostate cancer risk : strong confirmation of functional promoter SNP
- 2005
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Ingår i: Human Genetics. - Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Karolinska Inst, Ctr Genom & Bioinformat, Stockholm, Sweden. Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD USA. CLINTECH, Karolinska Inst, Ctr Oncol, Stockholm, Sweden. : SPRINGER. - 0340-6717 .- 1432-1203. ; 118:3-4, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- The E-cadherin gene (CDH1) has been proposed as a prostate cancer (PC) susceptibility gene in several studies. Aberrant protein expression has been related to prognosis and progression in PC. In addition, a functional promoter SNP (rsl6260) has been found to associate with PC risk. We performed a comprehensive genetic analysis of CDH1 by using the method of haplotype tagged SNPs in a large Swedish population-based case-control study consisting of 801 controls and 1,636 cases. In addition, Swedish PC families comprising a total of 157 cases sampled for DNA were analyzed for selected SNPs. Seven SNPs, including the promoter SNP rsl6260, that captured over 96% of CDH1 haplotype variation were selected as haplotype tagging SNPs and analyzed for associated PC risk. We observed significant confirmation of rsl6260 (P=0.003) for cases with a positive family history of PC (FH+) both in an independent case-control population and in PC families. In addition, a common haplotype (HapB, 25%) including the variant allele of rsl6260 was associated (P=0.004) with PC risk among FH+ cases. The promoter SNP rsl6260 as well as HapB were significantly transmitted to affected offspring in PC families. We report strong confirmation of the association between PC risk in FH+ cases and a functional CDH1 promoter SNP in an independent population. In conjunction with the biological importance of CDH1 our findings encourage further evaluation of genetic variation in CDH1 in relation to PC etiology. Due to the difficulties in replication of genetic association studies. this finding is unusual and novel.
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| 46. |
- Muller, L. S. O., et al.
(författare)
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Magnetic resonance imaging of the knee for chronological age estimation-a systematic review
- 2023
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Ingår i: European Radiology. - 0938-7994. ; 33:98, s. 5258-5268
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionRadiographs of the hand and teeth are frequently used for medical age assessment, as skeletal and dental maturation correlates with chronological age. These methods have been criticized for their lack of precision, and magnetic resonance imaging (MRI) of the knee has been proposed as a more accurate method. The aim of this systematic review is to explore the scientific and statistical evidence for medical age estimation based on skeletal maturation as assessed by MRI of the knee.Materials and methodsA systematic review was conducted that included studies published before April 2021 on living individuals between 8 and 30 years old, with presumptively healthy knees for whom the ossification stages had been evaluated using MRI. The correlation between "mature knee" and chronological age and the risk of misclassifying a child as an adult and vice versa was calculated.ResultsWe found a considerable heterogeneity in the published studies -in terms of study population, MRI protocols, and grading systems used. There is a wide variation in the correlation between maturation stage and chronological age.ConclusionData from published literature is deemed too heterogenous to support the use of MRI of the knee for chronological age determination. Further, it is not possible to assess the sensitivity, specificity, negative predictive value, or positive predictive value for the ability of MRI to determine whether a person is over or under 18 years old.
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