| 1. |
- Baird, Denis A., et al.
(author)
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Identification of Novel Loci Associated With Hip Shape : A Meta-Analysis of Genomewide Association Studies.
- 2019
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In: Journal of Bone and Mineral Research. - : Wiley-Blackwell. - 0884-0431 .- 1523-4681. ; 34:2, s. 241-251
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Journal article (peer-reviewed)abstract
- We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
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| 2. |
- Dörpinghaus, Jens, et al.
(author)
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A novel link prediction approach on clinical knowledge graphs utilizing graph structures
- 2022
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In: Proceedings of the of the 17th Conference on ComputerScience and Intelligence Systems. - : Polish information processing society (PTI). - 9788396242396 - 9788396589705 - 9788396589712 ; , s. 43-52
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Conference paper (peer-reviewed)abstract
- This paper presents a novel approach towards link prediction in clinical knowledge graphs. They play a central role in linking data from different data sources and are widely used in big data integration, especially for connecting data from different domains. We present a knowledge graph initially built on data from a clinical trial on Spinocerebellar ataxia type 3 (SCA3), which is a rare autosomal dominant inherited disorder. The contributions of this paper are (1) to create a feasible data representation schema capable of handling clinical imaging data in a knowledge graph and to (2) convert the data efficiently into a knowledge graph. Due to the limited amount of patient-nodes usually common methods for link prediction and graph embeddings are problematic and thus we will (3) present a novel approach for link prediction utilising graph structures and Conditional Random Fields. In addition, we present (4) an extensive evaluation underlining the importance of (a) data management and (b) further research on link prediction using graph structures.
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| 3. |
- Fechner, Richard, et al.
(author)
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Ensemble of HMMs for Sequence Prediction on Multivariate Biomedical Data
- 2024
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In: BioMedInformatics. - : MDPI. - 2673-7426. ; 4:3, s. 1672-1691
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Journal article (peer-reviewed)abstract
- Background: Biomedical data are usually collections of longitudinal data assessed at certain points in time. Clinical observations assess the presences and severity of symptoms, which are the basis for the description and modeling of disease progression. Deciphering potential underlying unknowns from the distinct observation would substantially improve the understanding of pathological cascades. Hidden Markov Models (HMMs) have been successfully applied to the processing of possibly noisy continuous signals. We apply ensembles of HMMs to categorically distributed multivariate time series data, leaving space for expert domain knowledge in the prediction process.Methods: We use an ensemble of HMMs to predict the loss of free walking ability as one major clinical deterioration in the most common autosomal dominantly inherited ataxia disorder worldwide.Results: We present a prediction pipeline that processes data paired with a configuration file, enabling us to train, validate and query an ensemble of HMMs. In particular, we provide a theoretical and practical framework for multivariate time-series inference based on HMMs that includes constructing multiple HMMs, each to predict a particular observable variable. Our analysis is conducted on pseudo-data, but also on biomedical data based on Spinocerebellar ataxia type 3 disease.Conclusions: We find that the model shows promising results for the data we tested. The strength of this approach is that HMMs are well understood, probabilistic and interpretable models, setting it apart from most Deep Learning approaches. We publish all code and evaluation pseudo-data in an open-source repository.
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| 4. |
- Garcia-Moreno, Hector, et al.
(author)
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Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3
- 2022
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:8, s. 2439-2452
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.
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| 5. |
- Wang, Li-San, et al.
(author)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Journal article (peer-reviewed)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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