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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.
The aim of this study was to provide robust evidence on the long-term use of non-nutritive sweetened (NNS) beverages on weight management, by comparing NNS beverages and water during 1 year of assisted weight management followed by a voluntary, unassisted 1-year extension. In this parallel-group, open-label, controlled equivalence trial, 493 adults with BMI 27–35 kg/m2 who regularly consumed cold beverages were randomised 1:1 to water (n 246) or NNS beverages (n 247). Participants joined a group behavioural weight-management programme comprising assisted meetings weekly (12-week weight-loss phase) then monthly (40-week weight-maintenance phase), followed by unassisted monitoring for 52 weeks with a final meeting at week 104. The final 52-week unassisted phase was completed by 220 participants (water: n 117; NNS beverages: n 103), 27·7 % of whom were NNS beverage-naïve (naïve was defined as NNS beverages comprising ≤ 25 % of beverages in the 5 years before screening). In the unassisted monitoring phase, the primary endpoint was weight change from baseline at week 104 (equivalence: two-sided P > 0·05). Participants consuming water maintained a weight loss of 3·7 kg over 104 weeks, compared with 4·8 kg with NNS beverages; the between-group difference was not significant. After the final 52-week unassisted phase of the 104-week behavioural weight-management programme, water and NNS beverages showed equivalence regarding weight change from baseline. Our findings suggest people can lose weight and maintain it for 2 years, when drinking either NNS beverages or water and taking part in weight-management programmes.
This trial is registered with ClinicalTrials.gov: NCT02591134.
Of all the major thinkers of the Scottish Enlightenment, Thomas Reid was the most closely involved with university life as a librarian, teacher and administrator. The writings collected here illustrate his thinking about the aims, scope and value of a liberal education, as well as the foundations of his common sense philosophy.
With an editorial introduction which both recounts his academic career at King’s College Aberdeen and the University of Glasgow and traces the connections between his educational ideals and his philosophical doctrines, the volume illuminates Reid’s distinctive contribution to the formation of Scotland’s ‘democratic intellect’.
Oratio habita in Auditorio publico Collegij Regij Abredonensis 9 April 1753.
Auditores
[1] Consilium mihi est pauca, debita cum verecundia, Iudicio vestro permittere de Legibus Philosophandi. Et cum hæc sit Materia a Philosophis plerumque intacta, vel lævi manu perstricta eo magis Auditorum Doctorum Candorem & Indulgentiam exposcere æquum est, avia loca, nullius fere trita solo peragranti.
[2] In omni Arte, et in omni quidem Opere consilio et Ratione in certum finem destinato, necesse est ut sint Leges Artis, Leges Operis ex ipsius Natura & Fine petitæ, quas ultra citrave rectum verum & utile in illa Arte vel opere nequit Consistere. Ita esse in Artibus & Operationibus mechanicis Vulgo notum est. Idem obtinere in Artibus Elegantioribus Pingendi Cælandi, in Architectura Statuaria Musica consentiunt harum Artium periti. Rhetoricæ Compositionis et Pronounciationis Leges tradiderunt Rhetores. Artis Imperatoriæ & Administrationis Politic‹æ› Leges plurimi magni Nominis Authores. Et quamvis Poesis divinum Afflatum præ se ferat‹,› nihilo minus hanc ipsam Legibus constringere et divino furore percitis Cancellos opponere ausus fuit olim Stagirita & post eum alij cum magno tum Poetarum tum Philosophorum plausu.
[3] Imo Summus Poeta omnium Artifex atque Rector Omnipotens dum Rerum primordia conderet ipse sibi Leges dixit Sapientiæ & Bonitati suæ congruas; & Mundum tum Materialem tum Rationalem regere perstat Legibus Sapientissimis et Benignissimis quarum Investigatio Philosophiæ precipua & Nobilissima pars est.
1 The Elements of Geography so far as they can be delivered in a Historical or Narrative Way Containing 1 The General Parts of the Globe. The Zones Climates & the Aspects of the Heavens in them
2 The Division of the Earth into Land and Water. the Names of Seas Islands Continents Countrys both ancient & Modern.
3 A very few of the Most remarkable Things belonging to each Country or City. Such as their being the Seat of such an Empire the birth place of Such a Great Man the Scene of Such a Battle or famous for the Invention of Such an Art. Some Character of this kind ought to be annexed to every Remarkable place which helps the memory and at the Same time conveys the knowledge of many of the Most Remarkable facts. Which Stick best in the Memory when annexed to the place that is Related to them.* The Books must be mentioned that give the best account either of the Ancient or Modern State of these Countrys & Some Idea of those books given & the same is to be understood with respect to all the Other parts of Learning Contained in this Course*
4 An Account of the Trade Winds & the most Remarkable things relating to the Weather in Different Countrys also the Most remarkable Ranges of Mountains their height Volcanos Earth Quakes &c
The History of things Under Ground 1 Mettals where & how found The Propertys of Ores the ways of Refining them The properties of the Several Mettals.
Some farther Particulars of the Family of the Gregorys and Andersons, communicated by Dr. Thomas Reid, Professor of Moral Philosophy in the University of Glasgow, a Nephew of the late Dr. David Gregory Savilian Professor at Oxford.
Some account of the family of the Gregorys at Aberdeen, is given in the Life of the late Dr. John Gregory prefixed to his works, printed at Edinburgh for A. Strahan and T. Cadell, London, and W. Creech, Edinburgh, 1788, in four small 8vo volumes.*
Who was the author of that Life, or whence he had his information, I do not know. I have heard it ascribed to Mr. Tytler the younger, whose father was appointed ‹556› one of the guardians of Dr. John Gregory's children.* Some additions to what is contained in it, and remarks upon it, is all I can furnish upon this subject.
Page 3. I know nothing of the education of David Anderson of Finzaugh.* He seems to have been a self-taught Engineer. Every public work which surpassed the skill of common artists, was committed to the management of David. Such a reputation he acquired by his success in works of this kind, that with the vulgar he got the by-name of Davie do a’ thing, that is in the Scottish dialect, David who could do every thing. By this appellation he is better known than by his proper name. He raised the great bells into the steeple of the principal church: he cut a passage for ships of burden through a ridge of rock under water, which crossed the entrance into the harbour of Aberdeen.*
To give a distinct account of the University of Glasgow, it is necessary to distinguish two periods of its existence, in which its constitution and appearance were extremely different; — the period before the reformation from Popery, and that which followed it; to which may be subjoined, the present state of the University, with such alterations, in the mode of conducting education, as the improvements in literature, and the state of society, have suggested. ‹2›
I. History of the University before the Reformation.
Origin. — At the request of King James II. Pope Nicolas V. granted a Bull,* constituting a “studium generale, tam in theologia, et in jure canonum et civili, quam in artibus, et in quacunque licita facultate,”* to continue in all time to come in the city of Glasgow; as being a notable place, and fit for the purpose, by the temperature of the air, and the plenty of all kinds of provisions for human life: and, by his apostolical authority, ordained, That its doctors, masters, readers, and students shall enjoy all the privileges, liberties, honours, exemptions, and immunities granted to the studium generale of his city of Bononia.* He likewise appointed William Turnbull,* then bishop of Glasgow, and his successors in that see, to be the rectors, called chancellors, of the said studium; and to have the same authority over the doctors, masters, and scholars, as the rectors have in the Studium Bononiense. — This Bull is dated at Rome the 7th of the month of January 1450, and the fourth year of his pontificate.*
The Love of Sensible Pleasure is the onely principle that is truly Natural & original to us. This Principle is in Separable from our Natures immutable & the same in all. There are several other principles in Grown Men Such as The Love of Honour, Riches, Virtue, Affection to the good of One's Countrey or Friends‹.› We Seek these things at first onely as the means of Procuring Sensible good to us. but when by long Experience we have found them Closely Connected with Sensible Good the Ideas of them come at last to be so Associated with the Idea of Good that we acquire an affection to them as good in themselves and seek them for their own Sake without any farther view‹.› These acquired Affections are different in different persons and in the same person may be Strengthned weakened or perhaps quite extinguished by Custom & Discipline‹.›
The Love of Sensible Pleasure seems indeed to be the onely Principle that operates in infants for Some time. But the Mind seems then to be in an infant State as well as the body.
… an edition is not the place to engage in passing critical debates or possibly idiosyncratic interpretations. It is a place for setting out any evidence on why a text came to be written, how it was written, what it alludes to, and if possible what contemporary, now-obscured question it was answering.
(Marilyn Butler, General Introduction to The Novels and Selected Works of Maria Edgeworth [1999–2003] vol. I, p. vii)
A ten-volume edition of an author who himself published only three book-length studies and a few smaller pieces may seem odd. In fact, the disproportion between Thomas Reid's published oeuvre and the hitherto unpublished material was central to the origins of the Edinburgh Edition of Thomas Reid and remains important to its rationale. For most of the time since his death but especially in twentieth- and twenty-first-century history of philosophy, Reid has mainly been known as a philosophers’ philosopher, a thinker who addressed central issues in epistemology, the philosophy of mind and the philosophy of action, and who did so, partly, in a classic in the genre, An Inquiry into the Human Mind, on the Principles of Common Sense, and, more wide-rangingly, in the less well known Essays on the Intellectual Powers of Man and Essays on the Active Powers of Man. Insofar as anything else by Reid was published, it was garnishment to those three works. This image of the pure philosopher was buttressed by Reid's reputation as the ablest contemporary critic of David Hume and, less flatteringly, as worth a dismissive remark by Immanuel Kant.
However, occasionally awareness of a much wider authorship surfaced, not least as ‘the Scottish Enlightenment’ became a flourishing subject of study in the 1980s.
As shown in Volume 9 of the Edinburgh Edition of Thomas Reid, after Reid's arrival in Glasgow in the summer of 1764 he immersed himself in the theoretical ideas and experimental enquiries of the chemists Joseph Black, William Irvine and, in the mid-1770s, Adair Crawford.1 While his relationship with Black was cordial, if somewhat distant, it seems that he was not directly involved in Black's research activities before the latter left for Edinburgh in 1766. His friendships with both Irvine and Crawford, on the other hand, were close, and he apparently served as a sounding board for his two young protégés. Reid's surviving manuscripts on chemistry attest to his engagement with the theoretical ideas of Irvine and Crawford. Furthermore, they also suggest that a manuscript fragment dealing with the measures of heat attributed to Irvine by his son, the physician and chemist William Irvine the younger, was, in fact, written by Reid.
The text transcribed below, to which I have given the title ‘The Measures of Heat’, was first published by William Irvine the younger in 1805. In his comments on the manuscript, Irvine highlights the incompleteness of the text, but expresses no doubt about the authorship of the manuscript.2 There are, however, good grounds upon which to question the younger Irvine's attribution of the fragment to his father. First, there is some overlap of wording and subject matter between the published fragment and a passage which dates from December 1787 in Reid's manuscript entitled ‘Of Heat’.