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- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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- 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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- Pfeiffer, Thomas, et al.
(författare)
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Predicting the replicability of social and behavioural science claims in a crisis: The COVID-19 Preprint Replication Project
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Replications are important for assessing the reliability of published findings. However, they are costly, and it is infeasible to replicate everything. Accurate, fast, lower-cost alternatives such as eliciting predictions could accelerate assessment for rapid policy implementation in a crisis. We elicited judgments from participants on 100 claims from preprints about an emerging area of research (COVID-19 pandemic) using an interactive structured elicitation protocol, and we conducted 29 new high-powered replications. After interacting with their peers, participant groups with lower task expertise (‘beginners’) updated their estimates and confidence in their judgements significantly more than groups with greater task expertise (‘experienced’). For experienced individuals, the average accuracy was 0.57 (95% CI: [0.53, 0.61]) after interaction, and they correctly classified 61% of claims; beginners’ average accuracy was 0.58 (95% CI: [0.54, 0.62]), correctly classifying 69% of claims. The difference in accuracy between groups was not statistically significant, and their judgments on the full set of claims were correlated (r=.48). These results suggest that both beginners and more experienced participants using a structured process have some ability to make better-than-chance predictions about the reliability of ‘fast science’ under conditions of high uncertainty. However, given the importance of such assessments for making evidence-based critical decisions in a crisis, more research is required to understand who the right experts in forecasting replicability are and how their judgements ought to be elicited.
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- Leung, Ying-Ying, et al.
(författare)
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Management of Peripheral Arthritis in Patients With Psoriatic Arthritis : An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations
- 2023
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 50:1, s. 119-130
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Forskningsöversikt (refereegranskat)abstract
- Objective We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations.Methods A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings.Results The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain.Conclusion Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations.
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- van Buul, Laura W, et al.
(författare)
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The Development of a Decision Tool for the Empiric Treatment of Suspected Urinary Tract Infection in Frail Older Adults: A Delphi Consensus Procedure.
- 2018
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1538-9375 .- 1525-8610. ; 19:9, s. 757-764
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Tidskriftsartikel (refereegranskat)abstract
- Nonspecific signs and symptoms combined with positive urinalysis results frequently trigger antibiotic therapy in frail older adults. However, there is limited evidence about which signs and symptoms indicate urinary tract infection (UTI) in this population. We aimed to find consensus among an international expert panel on which signs and symptoms, commonly attributed to UTI, should and should not lead to antibiotic prescribing in frail older adults, and to integrate these findings into a decision tool for the empiric treatment of suspected UTI in this population.A Delphi consensus procedure.An international panel of practitioners recognized as experts in the field of UTI in frail older patients.In 4 questionnaire rounds, the panel (1) evaluated the likelihood that individual signs and symptoms are caused by UTI, (2) indicated whether they would prescribe antibiotics empirically for combinations of signs and symptoms, and (3) provided feedback on a draft decision tool.Experts agreed that the majority of nonspecific signs and symptoms should be evaluated for other causes instead of being attributed to UTI and that urinalysis should not influence treatment decisions unless both nitrite and leukocyte esterase are negative. These and other findings were incorporated into a decision tool for the empiric treatment for suspected UTI in frail older adults with and without an indwelling urinary catheter.A decision tool for suspected UTI in frail older adults was developed based on consensus among an international expert panel. Studies are needed to evaluate whether this decision tool is effective in reaching its aim: the improvement of diagnostic evaluation and treatment for suspected UTI in frail older adults.
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- Mody, Cyrus C. M., et al.
(författare)
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Integrating research integrity into the history of science
- 2020
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Ingår i: History of Science. - : SAGE Publications. - 0073-2753 .- 1753-8564. ; 58:4, s. 369-385
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This introductory essay frames our special issue by discussing how attention to the history of research integrity and fraud can stimulate new historical and methodological insights of broader import to historians of science.
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- Roberts, Lissa L., et al.
(författare)
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Integrating the history of science into broader discussions of research integrity and fraud
- 2020
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Ingår i: History of Science. - : SAGE Publications. - 0073-2753 .- 1753-8564. ; 58:4, s. 354-368
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This introductory article frames our special issue in terms of how historicizing research integrity and fraud can benefit current discussions of scientific conduct and the need to improve public trust in science.
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| 29. |
- Saba, NF, et al.
(författare)
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Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer.
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| 30. |
- Saba, NF, et al.
(författare)
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Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer.
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- Woolf, Anthony D., et al.
(författare)
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Prevention of musculoskeletal conditions in the developing world
- 2008
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Ingår i: Best Practice & Research: Clinical Rheumatology. - : Elsevier BV. - 1532-1770 .- 1521-6942. ; 22:4, s. 759-772
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Tidskriftsartikel (refereegranskat)abstract
- Musculoskeletal conditions are an increasingly common problem across the globe due to increased longevity and increased exposure to risk factors such as obesity and lack of physical activity. The increase is predicted to be greatest in developing countries, and there is thus an urgent need for the implementation of strategies and policies that will prevent and control these conditions. The ideal is modification of the risk factors in the whole community, and this will have wide-ranging health benefits as these risk factors are common to other major conditions. Changing people's behaviour is a challenge; targeting those at highest risk is potentially more effective, providing that there are both affordable ways of identifying those at risk and affordable interventions. Early intervention in those with a condition such as rheumatoid arthritis is probably the most cost-effective approach, but requires diagnostic capacity - in clinical skills and/or technology - as well as access to care. There is now much evidence for what can be achieved, but the challenge is how to implement these different strategies in developing countries where there are competing priorities for limited resources. The key strategy is to raise awareness among the public, health professionals, and policy makers of the importance of musculoskeletal health, of what can be achieved by prevention and treatment, and to ensure that policies reflect this. It is also necessary to educate the public to know when to seek care, and health-care workers to recognize the early signs of musculoskeletal conditions.
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