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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.
The popular genre of medieval romance explored in its physical, geographical, and literary contexts. The essays in this volume take a representative selection of English and Scottish romances from the medieval period and explore some of their medieval contexts, deepening our understanding not only of the romances concerned but also of the specific medieval contexts that produced or influenced them. The contexts explored here include traditional literary features such as genre and rhetorical technique and literary-cultural questions of authorship, transmission and readership; but they also extend to such broader intellectual and social contexts as medieval understandings of geography, the physiology of swooning, or the efficacy of baptism. A framing context for the volume is provided by Derek Pearsall's prefatory essay, in which he revisits his seminal 1965 article on the development of Middle English romance. Rhiannon Purdie is Senior Lecturer in English, University of St Andrews; Michael Cichon is Associate Professor of English at St Thomas More College in the University of Saskatchewan.
No literature exists in a vacuum. Meaning is generated through context, or rather contexts, since there will always be several that apply at any one point and these will change and multiply over time. This is no less true of medieval romance than of any other genre of literature, and no single study is likely to address all of the relevant contexts for a genre as widespread and popular – in sheer numbers and variety of readers – as medieval romance. The aim of the present collection of essays is to take a selection of English and Scottish romances from the medieval period and explore some medieval contexts that might deepen our understanding of them. The contexts explored here include more traditional literary concerns with questions of genre and rhetorical technique or literary-cultural questions of authorship, transmission and readership, but they also extend to such broader intellectual and social contexts as medieval understandings of geography, or the physiology of swooning, or the efficacy of baptism. This is a two-way process: the romances studied here are illuminated by the various contexts in which the volume's contributors set them, but so too are those contexts enriched and altered by romance's interaction with them. The medieval audience for romance was relatively broad and varied: old and young, women and men, clerical and lay, nobility, gentry, merchants and those who could not afford – perhaps could not read – their own manuscript or print copy of a Middle English romance.
At first glance, the Older Scots romance Eger and Grime seems to be a stereotypical medieval tale about prowess, revenge and love. Perhaps this is why Eger and Grime has not been extensively studied. In general, medieval romances entertain, and this is certainly true of Eger and Grime. However, romances also convey, strengthen and uphold social bonds, opinions, prejudices, hopes and fears. In this they function very much like proverbs. Proverbial sayings ‘propose a world of moral implications to those who pause to consider them’. By pausing thus over the proverbs deployed in romances, one may gain a better understanding of what the authors of these texts were trying to convey. From the thirty categories of paroemial segment (proverbs and proverbial phrases) identified in Eger and Grime by Bartlett Whiting in his two-part article ‘Proverbs and Proverbial Sayings from Scottish Writings before 1600’, supplemented by twelve not noted by Whiting, I have identified groups of proverbs in the romance which exhibit some common characteristics. This chapter will consider three of these groups – proverbial comparisons; proverbs touching on the condition of women; and reciprocity. The proverbial comparisons are fairly conventional phrases one would expect to find in a tale of knights, combat and love, but should not be overlooked for this reason. Traditional phraseology generates meaning by deploying well-established conventions that function similarly each time they are used.
ELEMENTS of the erotic appear in much medieval Welsh literature, such as the romantic heroic exploits depicted in the three Welsh Arthurian Romances and more playfully shocking themes, as evidenced by Dafydd ap Gwilym's complaint to his penis and Gwerfel Mechain's response in praise of her genitals. The Fourth Branch of the Mabinogi is no exception to this penchant for the passionate, replete with its references to sexual encounters that both spark the erotic imagination and serve an instructive social purpose. Recounting erotic situations in and of themselves is not the redactor's primary objective: he uses the erotic potential of his tale to convey the message that misapplied passion and lust result in the breakdown of society. Suggestive rather than descriptive, the erotically charged passages in the Fourth Branch illustrate some sort of failure of social order, and this is no surprise: transgressive love is a staple of medieval literature.
The Fourth Branch, with its symbolic interpretations of everyday social obligations, communicates the necessity of maintaining social bonds and suggests that trespass of social and familial obligations requires redress and reparation. Myth communicates a number of sentiments – rules for social interaction, ethical conduct and even religious beliefs – and enforces a moral order necessary for group survival. As Roberta Valente notes in her Merched y Mabinogi, the Four Branches contain guidelines of behaviour that depend on both an individual's obedience to such codes and that individual's ability to interpret difficult situations where principles conflict or are non-existent.
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