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- Menden, MP, et al.
(author)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Journal article (peer-reviewed)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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- Brownstein, Catherine A., et al.
(author)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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In: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Journal article (peer-reviewed)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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- Huijser, Erika, et al.
(author)
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Serum IFNα2 measured by single-molecule array associates with systemic disease manifestations in Sjögren's syndrome
- 2022
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In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 61:5, s. 2156-2166
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Type I IFN (IFN-I) activation is a prominent feature of primary SS (pSS), SLE, and SSc. Ultrasensitive single-molecule array (Simoa) technology has facilitated the measurement of subfemtomolar concentrations of IFNs. Here, we aimed to measure IFNα2 in serum from pSS, SLE, and SSc using a Simoa immunoassay and correlate these levels to blood IFN-stimulated gene (ISG) expression and disease activity.METHODS: Serum IFNα2 was measured in patients with pSS (n = 85; n = 110), SLE (n = 24), and SSc (n = 23), and healthy controls (HC; n = 68) using an IFNα Simoa assay on a HD-X analyser. IFN-I pathway activation was additionally determined from serum by an IFN-I reporter assay and paired samples of whole blood ISG expression of IFI44, IFI44L, IFIT1, IFIT3, and MxA by RT-PCR or MxA-ELISA.RESULTS: Serum IFNα2 levels were elevated in pSS (median=61.3 fg/mL) compared to HC (median ≤5 fg/mL; p < 0.001) and SSc (median=11.6 fg/mL; p = 0.043), lower compared to SLE (median=313.5 fg/mL; p = 0.068), and positively correlated with blood ISG expression (r = 0.66-0.94; p < 0.001). Comparable to MxA-ELISA (AUC=0.93), IFNα2 measurement using Simoa identified pSS with high ISG expression (AUC=0.90) with 80-93% specificity and 71-84% sensitivity. Blinded validation in an independent pSS cohort yielded a comparable accuracy. Multiple regression indicated independent associations of autoantibodies, IgG, HCQ treatment, cutaneous disease and history of extraglandular manifestations with serum IFNα2 concentrations in pSS.CONCLUSION: Thus, Simoa serum IFNα2 reflects blood ISG expression in pSS, SLE, and SSc. In light of IFN-targeting treatments, Simoa could potentially be applied for patient stratification or retrospective analysis of historical cohorts.
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- Groufh-Jacobsen, S., et al.
(author)
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Food literacy and diet quality in young vegans, lacto-ovo vegetarians, pescatarians, flexitarians and omnivores
- 2023
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In: Public Health Nutrition. - 1368-9800. ; 26:12, s. 3051-3061
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Journal article (peer-reviewed)abstract
- Objective: To investigate whether food literacy competencies and diet quality vary between 16-to-24-year-olds vegans, lacto-ovo vegetarians, pescatarians, flexitarians and omnivores and to assess whether food literacy is associated with diet quality. Design: Cross-sectional study. Food literacy (general nutrition knowledge, critical nutrition literacy and food skills) and diet quality were measured using an electronic questionnaire. Setting: Southern Norway, September 2021 - March 2022. Participants: Healthy 16-24-year-olds (n 165). Results: Overall, the mean general nutrition knowledge score was moderate (480 out of 670); the lowest mean score was found in omnivores and the highest in flexitarians (456 v. 515) (P= 0034). The mean score of critical nutrition literacy was also moderate (37 out of 50); vegans showed higher scores compared to other dietary practices (P = 0018). No difference was observed in food skills between the different dietary practices. The overall median diet quality score was 460 out of 800, lowest in omnivores and highest in vegans (420 v. 560) (P=< 0001). In multivariate regression analyses, general nutrition knowledge, food skills and vegan dietary practice were significantly associated with higher diet quality. Conclusions: We found moderate levels of food literacy across all dietary practices. The food literacy competencies, general nutrition knowledge and food skills were associated with higher diet quality in our sample. Omnivores showed both the lowest general nutrition knowledge level and lowest diet quality scores. In contrast, both flexitarians and vegans scored highest on general nutrition knowledge and diet quality scores, despite being one of the less restrictive and one of the strictest plant-based dietary practices, respectively.
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- Jayne, David R W, et al.
(author)
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Glomerulonephritides.
- 2014
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In: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 29 Suppl 3, s. 27-29
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Conference paper (peer-reviewed)
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