| 1. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 2. |
- Bott, Lukas Thomas, et al.
(författare)
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Coulomb dissociation of O-16 into He-4 and C-12
- 2023
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Ingår i: NUCLEAR PHYSICS IN ASTROPHYSICS - X, NPA-X 2022. - : EDP Sciences. - 2100-014X. ; 279
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Konferensbidrag (refereegranskat)abstract
- We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4.
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| 3. |
- Swen, JesseJ, et al.
(författare)
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A 12-gene pharmacogenetic panel to prevent adverse drug reactions : an open-label, multicentre, controlled, cluster-randomised crossover implementation study
- 2023
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 401:10374, s. 347-356
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Tidskriftsartikel (refereegranskat)abstract
- Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.Findings: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51.4 % female, 48.6% male; 97.7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1.6%] of the study group and 47 [1.3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11.0%] in the study group and 285 [7.9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21 center dot 0%) of 725 patients in the study group and 231 (27.7%) of 833 patients in the control group (odds ratio [OR] 0 center dot 70 [95% CI 0 center dot 54-0 center dot 91]; p=0.0075), whereas for all patients, the incidence was 628 (21.5%) of 2923 patients in the study group and 934 (28. 6%) of 3270 patients in the control group (OR 0.70 [95% CI 0.61-0.79]; p <0.0001).Interpretation: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.
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