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The predictive power of polygenic scores (PGSs) for lithium treatment response in bipolar disorder remains limited.
Aims
To enhance the prediction of lithium responsiveness by developing a multi-trait PGS (mt-PGS) combining genetic information from multiple phenotypes implicated in lithium response and/or bipolar disorder aetiology.
Method
We analysed data collected from bipolar disorder patients who had received lithium treatment for at least 6 months and participated in the International Consortium on Lithium Genetics study (N = 2367). The Alda scale was used to assess lithium responsiveness, and treatment outcome was defined as continuous total Alda score (0–10) and categorical outcome (favourable ≥7 versus unfavourable response). PGSs were calculated for 60 phenotypes grouped into 5 clinical–biological clusters: psychiatric and behavioural (#23 phenotypes), cardiometabolic (#17), autoimmune/inflammatory (#5), neurocognitive (#8) and renal function (#7). We applied cross-validated machine learning regression approaches in both outcomes within each cluster, with the selected features from each cluster subsequently combined to construct the final mt-PGS models. Model performance was assessed using explained variance (R2) for the continuous outcome, and both McFadden’s pseudo-R2 and standard classification model parameters for the categorical outcome.
Results
mt-PGS explained between 5.70% (continuous outcome) and 9.11% (categorical outcome) of the interindividual variability in lithium responsiveness. Classification accuracy (area under the curve) for the categorical outcome was 68.24% (95% CI: 64.98–71.66), with a Brier score of 0.257. Of the 5 clusters, the PGSs for psychiatric and behavioural phenotypes were most strongly associated with lithium responsiveness, accounting for 3.67–6.52% of its variability.
Conclusions
By integrating PGSs for multiple relevant phenotypes, predictive accuracy for lithium response improved substantially compared with single-trait methods. Future research incorporating larger, more diverse populations and combining genetic scores with clinical data holds promise for further enhancing prediction and advancing clinical implementation.
In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.
Methods:
A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.
Results:
We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.
Conclusion:
The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
With the recent discovery of a dozen dusty star-forming galaxies and around 30 quasars at z > 5 that are hyper-luminous in the infrared (μ LIR > 1013 L⊙, where μ is a lensing magnification factor), the possibility has opened up for SPICA, the proposed ESA M5 mid-/far-infrared mission, to extend its spectroscopic studies toward the epoch of reionisation and beyond. In this paper, we examine the feasibility and scientific potential of such observations with SPICA’s far-infrared spectrometer SAFARI, which will probe a spectral range (35–230 μm) that will be unexplored by ALMA and JWST. Our simulations show that SAFARI is capable of delivering good-quality spectra for hyper-luminous infrared galaxies at z = 5 − 10, allowing us to sample spectral features in the rest-frame mid-infrared and to investigate a host of key scientific issues, such as the relative importance of star formation versus AGN, the hardness of the radiation field, the level of chemical enrichment, and the properties of the molecular gas. From a broader perspective, SAFARI offers the potential to open up a new frontier in the study of the early Universe, providing access to uniquely powerful spectral features for probing first-generation objects, such as the key cooling lines of low-metallicity or metal-free forming galaxies (fine-structure and H2 lines) and emission features of solid compounds freshly synthesised by Population III supernovae. Ultimately, SAFARI’s ability to explore the high-redshift Universe will be determined by the availability of sufficiently bright targets (whether intrinsically luminous or gravitationally lensed). With its launch expected around 2030, SPICA is ideally positioned to take full advantage of upcoming wide-field surveys such as LSST, SKA, Euclid, and WFIRST, which are likely to provide extraordinary targets for SAFARI.
Our current global food system – from food production to consumption, including manufacture, packaging, transport, retail and associated businesses – is responsible for extensive negative social and environmental impacts which threaten the long-term well-being of society. This has led to increasing calls from science–policy organizations for major reform and transformation of the global food system. However, our knowledge regarding food system transformations is fragmented and this is hindering the development of co-ordinated solutions. Here, we collate recent research across several academic disciplines and sectors in order to better understand the mechanisms that ‘lock-in’ food systems in unsustainable states.
Replacement phenomena in amblygonite–montebrasite in rare-element pegmatites from the Karibib-Usakos area, Namibia, have been investigated using the electron microprobe. The first African occurrence and analysis of the very rare mineral natromontebrasite NaAl(PO4)(OH,F) is reported from the Daheim pegmatite. In the Okatjimukuju pegmatite, montebrasite has been replaced by a number of phases including crandallite CaAl3(PO4)2(OH)5·H2O and brazilianite NaAl3(PO4)2(OH)4. In one example, montebrasite has been almost completely replaced by brazilianite which has also been found to contain not only crandallite but also its solid solution analogues: goyazite SrAl3(PO4)2(OH)5·H2O and gorceixite BaAl3(PO4)2(PO3OH)(OH)6. Apatite is common at the contacts with montebrasite and associated minerals and texturally is intimately intergrown with crandallite, goyazite and gorceixite at Okatjimukuju. The occurrence of these minerals offers insight into the chemistry of post-magmatic fluids in these pegmatites.
Previous studies of low-grade metamorphism in the Southern Uplands accretionary terrain indicated prehnite-pumpellyite facies/anchizone conditions developed throughout the area, except for local preservation of trench-slope sediments and an accreted seamount at zeolite facies/advanced diagenetic grade. New graptolite reflectance data are presented that show a general northward increase in temperature in the Southern Uplands. The results from two cross-strike traverses in the southern and central belts in contemporaneous sequences, using illite crystallinity, illite lateral spacing (bo) , and graptolite reflectance, indicate the development of systematic accretion-related low-grade metamorphism. Well-developed and constant anchizone conditions occur throughout the NE (Langholm) traverse, associated with common, F1 accretion-related folding and a regionally penetrative S1 cleavage. In the SW (Kirkcudbright) traverse, however, the youngest, last accreted packets are preserved at a transitional diagenetic stage and lack a penetrative S1 cleavage. Illite crystallinity, graptolite reflectance, and bo increase systematically northward through earlier accreted packets, reaching values of the NE traverse only at the northern end. The concomitant increase of bo with illite crystallinity suggests the relatively high P-low T trajectory characteristic of subduction zones. Integration of metamorphic and structural data relates increasing intensity of aceretion-related F1 folding, developmertt of S1 fabric, and onset of later fold phases to grade of metamorphism and structural level within the accretionary pile.
A combination of hydrogen and oxygen isotope analyses and fluid inclusion studies has defined the composition of fluids involved in the metamorphism of Lower Palaeozoic rocks in the English Lake District. Three fluid fields have been defined from secondary phases: 1, syn-burial metamorphic D-enriched fluids from epidote and chlorite at a temperature between 250 and 350°C; D-depleted fluid measured from groundmass and quartz inclusions; 3, a mixed magmatic-meteoric fluid with an intermediate H-isotopic composition estimated from W/R granite data and calculated from illite.
We have analysed a rare occurrence of orange-brown manganotantalite lamellae (visible in hand specimen), intergrown with microlite [(Ca,Na)2(Ta,Nb)2(O,OH,F)7], aggregates of ferrotapiolite, bismuth minerals and apatite to understand more about the mechanisms of crystal growth and secondary modification in Ta-rich minerals. The intergrowth occurs within amblygonite/montebrasite nodules near the quartz core of the highly fractionated rare-metal Li/Be/Ta pegmatite at Rubicon, Karibib, Namibia. Electron microprobe analyses show that manganotantalite lamellae are variable in composition. Primary microlite (Ta2O5 82%, 1.97 Ta a.p.f.u.) forms the matrix mineral between the lamellae. Textural relations suggest an exsolution origin for the lamellae. Manganotantalite is represented by three generations: (1) primary late magmatic; (2) disequilibrium exsolution lamellae; and (3) subsolidus replacement. Crystallization commenced with primary microlite and likely simultaneous intergrowth between ferrotapiolite and a first generation of late-magmatic primary manganotantalite with low Ta (1.1—1.5 a.p.f.u.). On cooling this was followed by exsolution of manganotantalite lamellae, generation (2) with low—medium Ta (1.27—1.7 a.p.f.u.). The replacement of microlite by a highly fractionated late-stage melt rich in Mn2+, Ca2+ with low Na+ finally produces a third generation (3) of manganotantalite with high Ta (1.72—1.99 a.p.f.u.) at the contact with microlite. Native bismuth and bismutite cut across microlite and pseudomorph lamellae as a final hydrothermal replacement. Apatite is ubiquitous at the contact with amblygonite. The stability field of microlite may be extended by incorporation of CaTa2O6-rynersonite and Ca2Ta2O7 — idealized, components in solid solution. However, rynersonite-CaTa2O6 with distorted octahedra has some structural templates which are similar to the structure of pyrochlore (microlite). Hence, via the perovskite/pyrochlore analogy, hypothetical exsolution of manganotantalite-type structures may occur from a microlite (pyrochlore) host by solid-state diffusion via metastable rynersonite-type intermediates. Such a mechanism has the potential to explain the crystallographically controlled intergrowth textures and the compositional heterogeneity.
Tidal flexure in ice shelf grounding zones has been used extensively in the past to determine grounding line position and ice properties. Although the rheology of ice is viscoelastic at tidal loading frequencies, most modelling studies have assumed some form of linear elastic beam approximation to match observed flexure profiles. Here we use density, radar and DInSAR measurements in combination with full-Stokes viscoelastic modelling to investigate a range of additional controls on the flexure of the Southern McMurdo Ice Shelf. We find that inclusion of observed basal crevasses and density dependent ice stiffness can greatly alter the flexure profile and yet fitting a simple elastic beam model to that profile will still produce an excellent fit. Estimates of the effective Young's modulus derived by fitting flexure profiles are shown to vary by over 200% depending on whether these factors are included, even when the local thickness is well constrained. Conversely, estimates of the grounding line position are relatively insensitive to these considerations for the case of a steep bed slope in our study region. By fitting tidal amplitudes only, and ignoring phase information, elastic beam theory can provide a good fit to observations in a wide variety of situations. This should, however, not be taken as an indication that the underlying rheological assumptions are correct.
Africa is experiencing a rapid increase in adult obesity and associated cardiometabolic diseases (CMDs). The H3Africa AWI-Gen Collaborative Centre was established to examine genomic and environmental factors that influence body composition, body fat distribution and CMD risk, with the aim to provide insights towards effective treatment and intervention strategies. It provides a research platform of over 10 500 participants, 40–60 years old, from Burkina Faso, Ghana, Kenya and South Africa. Following a process that involved community engagement, training of project staff and participant informed consent, participants were administered detailed questionnaires, anthropometric measurements were taken and biospecimens collected. This generated a wealth of demographic, health history, environmental, behavioural and biomarker data. The H3Africa SNP array will be used for genome-wide association studies. AWI-Gen is building capacity to perform large epidemiological, genomic and epigenomic studies across several African counties and strives to become a valuable resource for research collaborations in Africa.
D. R. Viete, G. J. H. Oliver and S. A. Wilde comment: First, we would like to commend Aoki et al. (2013) on a careful study and thought-provoking manuscript. Their interpretation of the Barrovian metamorphism as a fundamentally retrograde feature offers a refreshing alternative to the more conventional ‘peak-metamorphic’ models.