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- Millischer, V., et al.
(författare)
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Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden
- 2022
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Ingår i: Lancet Psychiatry. - 2215-0374. ; 9:6, s. 447-457
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Tidskriftsartikel (refereegranskat)abstract
- Background Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. Methods We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipolaR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipolaR, and the Swedish prescription registry. The median time between timepoints was 1.07 years for cohort 1 and 1.09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. Findings 2357 patients who were administered lithium (1423 women [60.4%] and 934 men [39.6%]; mean age 53.6 years [range 17-89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R-2]: R-cohort1(2)=0.41 and R-cohort2(2)=0.31; both p<0.0001), sex (R-cohort1(2)=0.0063 [p=0.045] and R-cohort2(2)=0.026 [p<0.0001]), eGFR (R-cohort1(2)=0.38 and R-cohort2(2)=0.0; both p<0.0001), comedication with diuretics (R-cohort1(2)=0.0058 [p=0.014] and R-cohort2(2)=0.0026 [p<0.0001]), and agents acting on the renin-aldosterone-angiotensin system (R-cohort1(2)=0.028 and R-cohort2(2)=0.015; both p<0.0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R-cohort1(2)=0.13 and R-cohort2(2)=0.15; both p<0.0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; beta=-0.053 [95% CI -0.071 to -0.034]; p<0.00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0.0014, corrected FDR=0.04) and cortex of the kidney (p=0.0015, corrected FDR=0.04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0.05, p=0.01), body-mass index (p value threshold: 0.05, p=0.00025), and blood urea nitrogen (p value threshold: 0.001, p=0.00043). The model based on six clinical predictors explained 61.4% of the variance in CLLi in cohort 1 and 49.8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59.32% to 59.36% in cohort 1 and from 49.21% to 50.03% in cohort 2 when including rs583503 and the four first principal components. Interpretation Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
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- Uusitalo, Mikko A., et al.
(författare)
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6G Vision, Value, Use Cases and Technologies from European 6G Flagship Project Hexa-X
- 2021
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Ingår i: IEEE Access. - 2169-3536 .- 2169-3536. ; 9, s. 160004-160020
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Tidskriftsartikel (refereegranskat)abstract
- While 5G is being deployed and the economy and society begin to reap the associated benefits, the research and development community starts to focus on the next, 6th Generation (6G) of wireless communications. Although there are papers available in the literature on visions, requirements and technical enablers for 6G from various academic perspectives, there is a lack of joint industry and academic work towards 6G. In this paper a consolidated view on vision, values, use cases and key enabling technologies from leading industry stakeholders and academia is presented. The authors represent the mobile communications ecosystem with competences spanning hardware, link layer and networking aspects, as well as standardization and regulation. The second contribution of the paper is revisiting and analyzing the key concurrent initiatives on 6G. A third contribution of the paper is the identification and justification of six key 6G research challenges: (i) “connecting”, in the sense of empowering, exploiting and governing, intelligence; (ii) realizing a network of networks, i.e., leveraging on existing networks and investments, while reinventing roles and protocols where needed; (iii) delivering extreme experiences, when/where needed; (iv) (environmental, economic, social) sustainability to address the major challenges of current societies; (v) trustworthiness as an ingrained fundamental design principle; (vi) supporting cost-effective global service coverage. A fourth contribution is a comprehensive specification of a concrete first-set of industry and academia jointly defined use cases for 6G, e.g., massive twinning, cooperative robots, immersive telepresence, and others. Finally, the anticipated evolutions in the radio, network and management/orchestration domains are discussed.
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- Uusitalo, Mikko A., et al.
(författare)
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Hexa-X: The european 6G flagship project
- 2021
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Ingår i: 2021 Joint European Conference on Networks and Communications and 6G Summit, EuCNC/6G Summit 2021. ; , s. 580-585
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Konferensbidrag (refereegranskat)abstract
- Hexa-X will pave the way to the next generation of wireless networks (Hexa) by explorative research (X). The Hexa-X vision is to connect human, physical, and digital worlds with a fabric of sixth generation (6G) key enablers. The vision is driven by the ambition to contribute to objectives of growth, global sustainability, trustworthiness, and digital inclusion. Key 6G value indicators and use cases are defined against the background of technology push, society and industry pull as well as objectives of technology sovereignty. Key areas of research have been formulated accordingly to include connecting intelligence, network of networks, sustainability, global service coverage, extreme experience, and trustworthiness. Critical technology enablers for 6G are developed in the project including, sub-THz transceiver technologies, accurate stand-alone positioning and radio-based imaging, improved radio performance, artificial intelligence (AI) / machine learning (ML) inspired radio access network (RAN) technologies, future network architectures and special purpose solutions including future ultra-reliable low-latency communication (URLLC) schemes. Besides technology enablers, early trials will be carried out to help assess viability and performance aspects of the key technology enablers. The 6G Hexa-X project is integral part of European and global research effort to help define the best possible next generation of networks.
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